One of the features of primate immunodeficiency viruses (HIVs and SIVs) that distinguishes them from other retroviruses is the array of "accessory" proteins they encode. Here, we discuss recent advances in understanding the interactions of the HIV-1 Nef, Vif, Vpu, and Vpr proteins with factors and pathways expressed in cells of the immune system. In at least three instances, the principal activity of the accessory proteins appears to be evasion from various forms of cell-mediated (or intrinsic), antiviral resistance. Broadly speaking, the HIV-1 accessory proteins modify the local environment within infected cells to ensure viral persistence, replication, dissemination, and transmission.