The purpose of expanded-access programs (EAPs) for antiretroviral therapy has been to allow patients without alternative treatment options to obtain drugs before formal Food and Drug Administration approval. Given the dramatic changes that have occurred in antiretroviral therapeutic approaches during the past 2 decades, we wish to review the history of antiretroviral EAPs and to propose an updated model for expanded access that would achieve maximal patient benefit and add useful knowledge that could guide treatment decisions in patients infected with multidrug-resistant human immunodeficiency virus.