The School's early history is intertwined with that of the first years of the University of Pennsylvania, which was established in 1740. Building on founder Benjamin Franklin's vision of combining a traditional and practical education, the College was the first colonial institution to teach the sciences, government and commerce, as well as classical subjects such as Latin, literature and philosophy. The College also had the colonies' only non-sectarian faculty. Graduates and trustees were instrumental in the development of the new nation, serving as members of the Continental Congress and signers of the Declaration of Independence and Constitution. By 1779, however, the state legislature considered the College a hotbed of loyalism and transferred its assets to the new University of the State of Pennsylvania. After a long legal battle, the two institutions were merged, creating the University of Pennsylvania in 1791.

The School's research mission was established in the 19th century, when the University transformed itself into a research institution. Its 1872 move to its present location provided several city blocks for research laboratories, and a large number of researchers were hired. A graduate division was established in 1882 with the appointment of a Faculty of Philosophy. The first fellowship for graduate study was established in 1885, and the first earned Ph.D. was awarded in physics in 1889. In 1892, the University began offering college courses for teachers, establishing the precursor of today's College of Liberal and Professional Studies, the Ivy League's oldest continuing education program.

The 20th century brought additional innovations. The College of Liberal Arts for Women was established in 1933, for the first time offering women a full-time, four-year undergraduate degree program in the liberal arts. The education of women and men was administered separately until 1974 when the College, the College for Women, the College of Liberal and Professional Studies, and the social science department of the Wharton School combined to become the Faculty of Arts and Sciences, which in 1976 changed its name to the School of Arts and Sciences.

This spirit of integration also led to the creation of several interdisciplinary programs, including History and Sociology of Science; Biological Basis of Behavior; and Philosophy, Politics, and Economics, as well as a number of regional studies programs. The School's atmosphere of innovation and collaboration has continued into the 21st century. In addition to its own interdisciplinary initiatives, SAS partners with Penn's other schools to offer programs such as international studies and business, biotechnology, and medical physics. An educational leader since its inception, the School's faculty includes Nobel laureates, Guggenheim fellows, Pulitzer Prize-winners, members of scholarly academies, and Fulbright, Rhodes, and Sloan scholars.

For additional details, see the University Archives web site.