The protease of HIV-1 is able to recognize many different sequences as substrates. Despite the diversity of these sequences, some of the determinants of HIV-1 protease specificity have been clarified by recent studies. These studies include the examination of known processing-site sequences, the use of polypeptides and native protein as substrates in vitro, and structural analyses of protease with bound polypeptide-based inhibitors. Mutations of the HIV-1 protease also have the potential to alter its specificity.