HIV-1 viral protein R (Vpr) is a small, highly conserved accessory protein encoded by the HIV genome that serves many functions in the viral life cycle. Vpr induces G2 cell cycle arrest, which is thought to indirectly enhance viral replication by increasing transcription from the LTR. Vpr has also been implicated in facilitating infection of nondividing cells, most notably macrophages. Because Vpr is a nucleo-cytoplasmic shuttling protein, its role in enhancing viral replication in macrophages may be mediated through enhanced entry of the HIV preintegration complex through the limiting nuclear pore. Free Vpr is detectable in the serum of patients, and in vitro studies implicate extracellular forms of Vpr as an effector of cellular responses mediated through its ability to transduce through intact cytoplasmic membranes. We review the biologic properties of Vpr, focusing on its mechanism of action, role in HIV replication, and significance for host pathogenesis.