The replication of retroviruses is dependent upon their ability to commandeer cellular factors at various stages in the replication cycle. Research over the past several years however, has revealed the presence of “cellular restrictions” that potently antagonize the replication of viruses such as HIV-1. For example, the Apobec 3 proteins are cytidine deaminases that compromise the formation and integrity of viral cDNA while Bst2/tetherin prevents detachment of budding viruses from the surface of the infected cell. In order to counteract these restrictions, primate lentiviruses have evolved accessory proteins: the Vif protein targets Apobec 3 for proteasomal destruction while Vpu mislocalizes Bst2/tetherin away from sites of virus budding. We have recently obtained evidence for novel restrictions that are expressed in cells of macrophage lineage. One restriction potently antagonizes retrovirus replication including the lentiviruses, HIV-1/2 and SIV as well as the gamma retrovirus, MLV. We have evidence that this restriction is counteracted by the viral accessory proteins Vpx/Vpr. These proteins commandeer a damaged DNA response protein (DDB1) to target the restriction to the proteasome. We have further obtained evidence that this restriction dictates the cell cycle dependence of retrovirus infection and is the obstacle to monocyte infection by retroviruses. Therefore when the restriction is neutralized, macrophages, which are normally refractory to MLV infection, are rendered permissive to MLV transduction. The second restriction antagonizes virus egress and is counteracted by the Vpu proteins of HIV-1/SIV. Given our increasing understanding of the function of the viral accessory proteins, they remain highly attractive targets for therapeutic intervention in HIV/AIDS.