Prior to 1996, all antiretroviral drugs approved for clinical use were nucleoside analogs directed against reverse transcriptase. The benefits are short-lived due to adverse effects and the emergence of resistant viral strains. The first of a diverse group of nonnucleoside reverse transcriptase inhibitors, nevirapine, has recently been approved. In addition, there are 3 newly available inhibitors of the viral protease enzyme, compounds which have shown impressive potency and a favorable therapeutic index. There is increasing evidence that combination antiretroviral therapy is more effective than any agent used alone. In this review, we summarize clinical experiences with these newer antiretroviral therapies and describe other novel agents that are in various stages of development.