The letters are set on the south side of a steep 581-foot (177 m) hill, part of the San Bruno Mountains, overlooking the city.

In order to create the appearance of straight, uniformly sized type despite the varied contour of the hillside, the letters are laid out using anamorphosis, ranging in height from 48 to 65 feet (15 to 20 m).

The letters for the first sign were carved directly into the hillside and filled with whitewash, consisting of a mixture of lime, white cement, and water; it was completed by November 22, 1923.

Local high school students were hired to maintain the sign by removing grass and applying fresh whitewash.

The sign is cited as a prime example of "civic boosterism"; the intention was to advertise the city's welcoming attitude toward industry.

The city's largest employer is now Genentech, which has promoted South San Francisco as "the birthplace of biotechnology".