Primate immunodeficiency viruses are highly specialized lentiviruses that have evolved to successfully infect and persist for the lifetime of the host. Despite encountering numerous potent antiviral factors, HIVs and SIVs are successful pathogens due to the acquisition of equally potent countermeasures in the form of accessory genes. The accessory gene Vpx encoded by HIV-2 and a subset of SIVs have a profound effect on the ability of lentiviruses to infect non-dividing cells, such as macrophages. Although most virus replication occurs in activated CD4+ T cells, myeloid lineage cells are natural targets of infection and play a central role in virus transmission, dissemination, and persistence. However, myeloid lineage cells are poorly sensitive to lentiviral infection due partly to the high-level expression of a host protein that regulates nucleic acid metabolism named SAMHD1. Degradation of SAMHD1 is induced by Vpx to eliminate this intrinsic antiviral factor. Importantly, SAMHD1 has also been implicated as a negative regulator of the innate immune response, so the interplay between SAMHD1 and Vpx is likely to have significant consequences for virus replication, persistence, and immune control.