HIV-1 infections and the resulting AIDS pandemic remain a global challenge in the absence of a protective vaccine and because of rapid selection of drug-resistant viral variants in response to all currently available antiviral therapies. The development of new and highly active antiviral agents would greatly facilitate effective clinical management of HIV-1 infections and delay the onset of AIDS. Recent advances in our understanding of intracellular immunity conferred by host cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) and the mechanism by which the virally encoded virion infectivity factor (Vif) protein induces their proteasomal degradation provide fresh opportunities for the development of novel antiviral treatments. Interestingly, the Vif-A3G and Vif-A3F interactions that overcome this host defense mechanism are structurally distinct and provide two potential targets for antiviral drug development. This review provides an overview of current knowledge of APOBEC3-Vif interactions and recent efforts to target these interactions for antiviral drug development.