Since the discovery of the human immunodeficiency viruses types 1 (HIV-1) and 2 (HIV-2) as the causative agents of acquired immunodeficiency syndrome (AIDS) (Barre-Sinoussi et al. 1983; Clavel et al. 1987; Papovic et al. 1984) and the isolation of related lentiviruses from several species of Old World monkeys, much has been learned about their biology and evolution. Based on genetic analysis, five distinct phylogenetic lineages of primate lentiviruses have now been identified: HIV-1/simian immunodeficiency virus (SIV)CPZ, HIV-2/SIVSM/SIVMAC, SIVAGM, SIVMND, and SIVSYK (for review see Johnson et al. 1991; Myers et al. 1992; Sharp et al. 1994). Like all retroviruses, primate lentiviruses are similar in structure and genomic organization. They contain gag, pol, and env genes that encode structural proteins essential for virion architecture (Gag), glycoproteins that enable the virus to recognize and infect its target (Env), and enzymatic proteins essential for processes of virus maturation, reverse transcription, and integration (Pol). While the genomic structure of all five lineages is conserved, differences exist in the composition of auxiliary genes: all five groups of viruses contain tat, rev, nef and vif all but SIVAGM contain vpr, only HIV-1/SIVSYK contains vpu, and only HIV-2/SIVSM/SIVMAC and SIVAGM viruses contain vpx (Cullen and Green 1990; Johnson et al. 1991). Primate lentiviruses have complex life cycles regulated by interactions of viral structural and accessory gene products as well as host factors (Cullen 1991). Viral accessory genes modulate replication, host cell tropism, chronic persistence, and pathogenicity. Defining the role of viral accessory genes is critical for understanding the natural history of infection and disease pathogenesis and thus represents a major goal in biomedical AIDS research. Moreover, knowledge of accessory protein function may facilitate the development of therapeutic and vaccine interventions. In this chapter the author reviews the present understanding of the role of Vpx in the HIV-2/SIV life cycle and the structure-function relationships that mediate incorporation of this protein into virions. Based on genetic and phylogenetic evidence indicating that in the HIV-2/ SIVSM/SIVMAC lineage vpxarose from a gene duplication of vpr and on the proposed reclassification of SIVAGM vpx to vpr (Tristem et al. 1990, 1992), for clarity this review will discuss vpx for only the HIV-2/SIVSM/SIVMAC group of viruses.