HIV produces structural, regulatory, and accessory proteins during viral replication in host cells. The accessory proteins include Nef, viral infectivity factor (Vif), viral protein R, and viral protein U or viral protein X. Although these accessory proteins are generally dispensable for viral replication in vitro, they are essential for viral pathogenesis in vivo. Consequently, there has been much interest in understanding how these accessory proteins function because this research may yield new antiviral targets to curb HIV pathogenesis in vivo. Therefore, this review highlights recent advances in understanding the HIV accessory proteins and emphasizes breakthrough insights into the elusive Vif protein and potential new targets for therapeutic intervention.