Robert Mapplethorpe established the Robert Mapplethorpe Foundation on May 27, 1988, the year before his death, to protect his work, to advance his creative vision and to promote the causes he cared about. Serving as the first president on its board of trustees, he established mandates of furthering the recognition of photography as an art form having the same respect as painting and sculpture and supporting AIDS and HIV medical research. In keeping with Mapplethorpe's wishes, The Robert Mapplethorpe Foundation has provided support for photography programming at the institutional level, including exhibitions, acquisitions and publications—in the form of financial grants or gifts of original Mapplethorpe artworks—at art institutions ranging from the world's major art museums to small university galleries.

In 1993, the Foundation provided a major gift to the Solomon R. Guggenheim Foundation to create the named Robert Mapplethorpe Gallery and to inaugurate the Guggenheim Museum's photography program. In addition to the financial component of its gift, the Foundation made a gift of a significant collection of more than 200 of the artist’s works.

Following the Guggenheim gift, the Foundation supported photography programs with major gifts resulting in three additional permanent galleries or facilities named for Robert Mapplethorpe—at the Whitney Museum of American Art, the Hessel Museum of Art at Bard College, in Annandale-on-Hudson, NY, and the National Portrait Gallery, part of the National Galleries of Scotland in Edinburgh.

In addition to the Guggenheim Museum, major public collections of Mapplethorpe’s work may be found in the Artist Rooms Collection jointly owned by the Tate Modern, London and the National Galleries of Scotland; at the Museum of Modern Art, New York, the Hessel Museum of Art, and the Kinsey Institute at Indiana University.

In 2011, the Mapplethorpe Foundation donated its archive to the Getty Research Institute and gave an encyclopedic collection of artworks to the J. Paul Getty Museum in partnership with the Los Angeles County Museum of Art. This gift established a comprehensive archive and collection, which is available to scholars.

In its early years, the Foundation prioritized its focus on HIV/AIDS research. It created important medical facilities and programs, including the Robert Mapplethorpe Laboratory for AIDS Research at Harvard Medical School in Boston, the Robert Mapplethorpe Residential Treatment Facility at Beth Israel Medical Center in New York, and the Robert Mapplethorpe Center for HIV Research at St. Vincent's Hospital, New York. The Foundation provided substantial financial support to the American Foundation for AIDS Research (AmFAR). It continues to support research initiatives and has provided funds to distinguished institutions such as the Rockefeller University as well as community based, drug trial organizations, including the AIDS Community Research Initiative of America (ACRIA).

The Foundation is dedicated to protecting and expanding Mapplethorpe’s artistic legacy by encouraging museum exhibitions all over the world. It publishes books and places his artworks from its considerable inventory, in important public and private collections around the world.