Recent advances in understanding the roles of the lentiviral accessory proteins have provided fascinating insight into the molecular biology of the virus and uncovered previously unappreciated innate immune mechanisms by which the host defends itself. HIV-1 and other lentiviruses have developed accessory proteins that counterattack the antiviral defenses in a sort of evolutionary battle. The virus is remarkably adept at co-opting cellular degradative pathways to destroy the protective proteins. This review focuses on recent advances in understanding three of the accessory proteins-virion infectivity factor (Vif), viral protein R (Vpr), and viral protein U (Vpu)-that target different restriction factors to ensure virus replication. These proteins may provide promising targets for the development of novel classes of antiretroviral drugs.