Since the first isolation of HIV-1 from a patient with generalized lymphadenopathy in 1983, great progress has been made in understanding the viral life cycle and the functional nuances of each of the nine genes encoded by HIV-1. Considerable attention has been paid to four small HIV-1 open reading frames, vif, vpr, vpu and nef. These genes were originally termed "accessory" because their deletion failed to completely disable viral replication in vitro. More than twenty years after the cloning and sequencing of HIV-1, a great deal of information is available regarding the multiple functions of the accessory proteins and it is well accepted that, collectively, these gene products modulate the host cell biology to favor viral replication, and that they are largely responsible for the pathogenesis of HIV-1. Expression of Vpr, in particular, leads to cell cycle arrest in G(2), followed by apoptosis. Here we summarize our current understanding of Vpr biology with a focus on Vpr-induced G(2) arrest and apoptosis.