San Francisco started rebuilding. The earthquake was a blessing for San Jose-born Amadeo Giannini (son of an Italian 49er who had opened a farm in the south bay) who in 1904 had founded Bank of Italy (later renamed Bank of America), which specialized in loans to the middle-class, and not only to the wealthy class. Most bankers shut down but Giannini instead extended loans to rebuild from his makeshift office on a North Beach wharf.

In 1907, the California Fruit Cannery Association (aka Del Monte) built the largest fruit and vegetable cannery in the world, located between Fisherman's Wharf and Ghirardelli's new chocolate factory (the old Pioneer Woolen Mills).

In 1907, investor Fred Swanton opened the Beach Boardwalk of Santa Cruz, halfway between San Francisco and Monterey, a complex of bathhouses, amusement park and restaurants, a “Coney Island of the West”.

San Francisco's Barbary Coast survived the earthquake. In fact, in 1908 the Dash became the first openly gay bar in the city, although it closed after a few months. But it didn't survive the press: in 1913 William Randolph Hearst's moralizing campaign in the San Francisco Examiner forced mayor James Rolph to crack down on Barbary Coast and forcing governor Hiram Johnson to enact the Red Light Abatement Act that de facto banned brothels from the state (the last ones of Barbary Coast were closed by Rolph in 1917).

Before and after the earthquake, San Francisco experienced waves of immigrants from southern Europe, notably from Italy. The Italians settled into the poorest neighborhood, North Beach, in the northwestern tip of the city, which became infamous for poverty, filth, and disease, the only ethnic enclave that was more disparaged than Chinatown. It was devastated by a new plague in 1907 and by tuberculosis in 1912-14.

The other Catholic group fared a lot better. The Irish Catholics, who during the Gold Rush era had been discriminated against no less than the Chinese by the largely Protestant business elite of San Francisco, were now fully integrated, and had even become a political force under the leadership of Edward Hanna, appointed archbishop in 1915.

In October 1913 the Lincoln Highway was dedicated, the first transcontinental highway, connecting the Atlantic coast to the Pacific coast, from Times Square in New York City to the newly created Lincoln Park in San Francisco, a journey of 5000 kilometers that the average car could complete in a month and that required carrying plenty of gasoline and full camping equipment because services for motorists were scarce. And there were only one million cars. The brain behind the project was Carl Fisher, an Indianapolis businessman whose previous claim to fame was to have opened the first car dealership in the country. In order to pave with concrete ("crushed rock") the unpaved sections, Fisher launched a nation-wide collection whose contributors eventually included inventor Thomas Edison, president Woodrow Wilson and former president Theodore Roosevelt. During World War I, in 1919, the army sent a military convoy from Washington to California that arrived after two months: they had to fix bridges that were not strong enough and muddy sections, but the convoy electrified the towns along the way. In 1925 the USA established the Interstate Highways Board that assigned numbers to highways, and the Lincoln Highway became US30, US1 and finally US40 in California.

After suffrage was granted to women in 1911, single women started feeling more empowered. In the 1890s single women were still mostly employed in the apparel business but in the 1910s they increasingly took jobs such as teachers, stenographers, typists, and telephone operators. Many were migrating from smaller towns to the cities. The very religious Lizzie Glide, the widow since 1906 of Sacramento cattle baron Joseph Glide, inherited vast land, ranches and homes in multiple counties of California, and her fortune was further increased when oil was discovered in Kern County, one of the places where she owned land. She used her wealth to become a San Francisco philanthropist: in 1913 she had built the Mary Elizabeth Inn, designed by Julia Morgan, to provide safe lodging to working single women.

In 1911 banking and shipping magnate James Rolph was elected mayor, after being endorsed by both Republican and Democratic parties, signaling that the business aristocracy was regaining control of San Francisco, at the same time that the progressives were celebrating Hiram Johnson's election to governor of California. Rolph, who developed a strong alliance with archbishop Hanna, remained mayor for 19 years, reelected for five consecutive terms, presiding over: the city-owned San Francisco Municipal Railway in 1912 (not owned by private investors like in all other major cities), the Lincoln Highway in 1913, the Panama-Pacific International Exposition of 1915, the inauguration of the new City Hall in 1916, the termination of Barbary Coast in 1917, the opening of the Twin Peaks tunnel in 1918 (the longest streetcar tunnel in the world), and the completion of the Hetch Hetchy dam in 1923.

These projects were all carried out by the Irishman whom Rolph had hired as city engineer: Michael O'Shaughnessy, a railway engineer who had arrived in 1885. By coincidence, the two enterprising men who solved the water issue for San Francisco and Los Angeles were both Irish: the school dropout William Mulholland and the college graduate Michael O'Shaughnessy, coming from two opposite ends of society. Without their work, the two iconic cities would not have grown as rapidly as they did.

Perhaps more importantly, it was under Rolph that San Francisco's scientific reputation improved. In 1914 the Hooper Foundation for Medical Research, second in size only to New York’s Rockefeller Institute, selected UC San Francisco (Parnassus Hill) as the site for its research center. Mindful of the plague epidemic of 1900, Rolph in 1915 appointed a scientist, William Hassler, as chief health officer. In the same year, UC San Francisco established a graduate program that trained students in bacteriology and chemistry. And so San Francisco, that had lacked the prestigious medical institutions of the East Coast, finally got a world-class medical institution, UC San Francisco, which began its ascent through the ranks of the life sciences (the future hub of biotech). When the "Spanish flu" started spreading in 1918, San Francisco was at the vanguard of research and experimentation, even using the Angel Island's immigration facilities and the Yerba Buena Island navy base to quarantine and study infected individuals. While scientists on the East Coast underestimated the epidemic and even mocked the panic, San Francisco became the first city to enact drastic measures, starting in October 1918 with the mandate for citizens to wear gauze masks in public Hassler was scientifically wrong, as scientist John Kyle at the University of Southern California pointed out, because the tiny influenza virus could easily penetrate the gauze mask, and in fact San Francisco ended up with the same death rate of any other major city, but the people of San Francisco celebrated two victories in November 1918: victory in World War I and the (accidental) decline of the flu. When the pandemic rebounded in 1819, Hassler, aware of the success of vaccines against rabies, typhoid and diphtheria, started administering the experimental flu vaccine developed at Tufts Medical School in Boston by Timothy Leary (uncle of the future psychedelic guru of the 1960s). That vaccine didn't work because it was based non German scientist Richard Pfeiffer's theory that a bacterium caused the flu (the influenza virus was only isolated in 1933 and the first flu vaccine was only developed in 1938), but again it allowed Rolph to promote San Francisco was a world-class progressive city. More than anything else, Rolph was successful in uniting the city around altruistic and patriotic ideals.

The local tradition of radio engineering led an immigrant to settle in San Francisco to conduct his experiments: in 1927 Philo Farnsworth, a stereotypical amateur who had been discovered in Utah by San Francisco's venture capitalists Leslie Gorrell and George Everson, carried out the first all-electronic television broadcast. His team included the young Russ Varian and Ralph Heintz. The power of RCA, however, was such that the Russian-born scientist Vladimir Zworkyn of their New Jersey laboratories was credited by the media with inventing television. Farnsworth's claim was defended in 1930 by his good San Francisco friend and lawyer Donald Lippincott who thus inaugurated the tradition of intellectual-property attorneys that would be crucial to the development of the Bay Area's high-tech industry. Nonetheless, in 1931 the company was sold to the Philadelphia Storage Battery Company (later renamed Philco), the main maker of home radios.

The 1920s were the age of the skyscraper for San Francisco, not a trivial feat for a city that had been destroyed by an earthquake. George William Kelham, who had designed San Francisco's Public Library in 1917 (which now houses the Asian Art Museum) and the campus of UC Los Angeles (1926), became the specialist of the genre, building the 21-story Standard Oil Building (1922), the 32-story Russ Building (1927), the 28-story Shell Building (1929), etc.

His main competitor was the San Francisco-native Timothy Pflueger, who designed the 26-story Pacific Telephone & Telegraph building (1925), the tallest building in San Francisco for 40 years, the 26-story Four Fifty Sutter Building (1929), and the art-deco Stock Exchange Tower (1930), including a stone relief by Ralph Stackpole, a mural by Diego Rivera and a lavishly decorated City Club on the tenth floor. He was also the master of the movie theater, designing the baroque Castro Theatre (1922), the Moorish-revival Alhambra Theatre (1926) and the tropical-themed Paramount Theatre (1931), the largest of California.

In the 1920 the Bohemian Club became an elite nation-wide men-only secret society that could be joined only by invitation, and the two-week retreat at the Bohemian Grove a way for some of the most powerful politicians and businessmen to get together. To become a member there was a 25-year waiting-list and the membership fee was expensive. Artists were no longer members for life, but invited as "performers" to entertain the lifelong members. Calvin Coolidge was the first president to become a member (1923), followed by all Republican presidents until George Herbert Bush (1989). An artist who was frequently invited was the sculptor Haig Patigian, an immigrant from Ottoman-occupied Armenia, who had made the friezes and sculptures for the Machinery Palace at the Panama-Pacific International Exposition.