For decades after the 1849 Gold Rush, San Francisco was the principal seaport and connection with the outside world for California and the West Coast. San Francisco's expansion and transformation into one of the most important cities in North America is attributable to the eminence of its port which, because of its sheltered location and deep water, became one of the best-suited on the Pacific Ocean.

The development of warehouses over a 120-year period along the southern waterfront provides a benchmark from which to view architectural and technological responses to the rapid changes of growing industrial nation state and city. The interdependence of architecture and history can be seen from a look at the evolution of warehouse forms along the southern waterfront. Unlike most other areas of the San Francisco waterfront, the South End District contains an extraordinary concentration of buildings from almost every period of San Francisco's maritime history. Several street fronts– such as Second, Third and Townsend– are characterized by solid walls of brick and reinforced concrete warehouses. With this harmony of scale and materials, the South End Historic District is clearly a visually recognizable place.

One-story warehouses were common in the nineteenth century but rare in the early twentieth due to the increasing cost of land. Two of the oldest warehouses in the historic district are one story in height: Hooper's Warehouse (1874) and the California Warehouse (1882). Their horizontal orientation is accentuated through the use of strong cornice lines with decorative brick patterns.

Multi-story buildings have been more common along the southern waterfront since the turn of the century. After 1906, almost all new warehouses were constructed to be at least three stories in height, and several warehouses on Second and Townsend Streets reached six stories. The invention of the forklift in the 1930s eliminated advantages which multi-story buildings enjoyed over single-story structures. Since 1945, almost all warehouses constructed in the United States have been one story in height. Many multi-story warehouses and industrial buildings have been converted to other uses or are vacant because they have become obsolete for most warehouse or industrial functions.

South End's period of historical significance, 1867 to 1935, comprises the era during which the waterfront became a vital part of the City's and nation's maritime commerce. The buildings of the South End Historic District represent a rich and varied cross-section of the prominent local architects and builders of the period. Four buildings remain from the nineteenth century; another four were constructed in the six-year interval preceding the 1906 earthquake. The majority of the buildings were erected between 1906 and 1929, a period during which trade along the waterfront increased dramatically.

Several events shaped this part of San Francisco. The building of Long Bridge in 1865 on the line of Fourth Street south to Point San Quentin or the Potrero district, opened up opportunities for new industrial development in the southern part of the city. The Second Street cut of 1869, through fashionable Rincon Hill, allowed access from downtown to the southern waterfront. The completion of the transcontinental railroad in 1869 (and the eventual extension of railway lines into the area) was the single most important event to impact the district. The fire of 1906 and the opening of the Panama Canal in 1914 were further impetuses to warehouse construction in this area, as were the seawall and the Belt Line Railway.

Prominent figures in San Francisco history have been associated with the district. William Ralston, founder of the Bank of California, builder of the Palace Hotel, and financier of San Francisco and the West, owned property in the district and was a major force in politically engineering the Second Street cut in 1869. William Sharon, a U.S. Senator from Nevada (1875–1881), acquired much of Ralston's estate and also co-owned and built the California Warehouse on the corner of Second and Townsend for Haslett and Bailey in 1882.

William P. Aspinwall founded the internationally important Oriental Warehouse (Pacific Mail Steamship Company) in this district during the Gold Rush. John Hooper built Hooper's South End Grain Warehouse at Japan and Townsend Streets in 1874 for California's lucrative grain trade. Hooper was a member of a family known particularly for its lumber trade, with large land holdings just south of the South End Historic District.

The leading warehouse firms in San Francisco were those of the Haslett and Lamb families. Samuel Haslett, a native of Ireland, came to San Francisco in the 1870s and became a partner with J.W. Cox at the Humboldt Warehouse on Rincon Point. Haslett's sons continued the business after his death, and Samuel Haslett IV is now president of the firm. Once nationally known in warehousing, the Hasletts built or are associated with seven warehouses in the district. George Lamb founded the South End Warehouse Company in 1905, and later co-founded the drayage and hauling firm of King and Company. South End operated six warehouses in the area at various times.

Charles Lee Tilden (1857–1950) built 111–113 Townsend, a Haslett warehouse, and the Overland warehouse at Third and Townsend Streets. Tilden, a highly successful business entrepreneur, also founded the East Bay Regional Park system in 1934. Charles Norton Felton (1828–1914), Senator, Congressman, and early developer of oil in California, is associated with warehouses at 275 Brannan Street and 601 Second Street.