Lopinavir is a protease inhibitor (PI) for the treatment of HIV infection that was specifically designed to overcome the shortcomings of earlier agents in this class. It is the only PI coformulated with ritonavir, whose pharmacological boosting effect results in a highly potent, well-tolerated, clinically effective antiretroviral agent with a high genetic barrier to resistance. Lopinavir/ritonavir is a recommended first-line option for antiretroviral-naive patients initiating PI-based therapy, and has an equally important role in the management of treatment-experienced individuals. Its favorable pharmacological and clinical characteristics have recently prompted investigators to explore its potential novel applications in HIV monotherapy and double-boosted regimens.