Despite the availability of 21 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens remain hampered by issues of toxicity, convenience, cost, incomplete viral suppression, and drug resistance. Expansion of the currently available therapeutic options through the reformulation of available agents, discovery of new compounds with antiretroviral activity, and the exploitation of novel drug targets are critical. This review describes the status of new nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. We also summarize new classes of antiretroviral therapy in clinical development including the attachment inhibitors, chemokine receptor antagonists, integrase inhibitors, and maturation inhibitors.