Vpr (Viral protein-R) of the Human Immunodeficiency Virus type-1 is a 14-kDa virion-associated protein, conserved in HIV-1, -2 and the Simian Immunodeficiency Virus (SIV). Vpr is incorporated into the virion, travels to the nucleus, and has multiple activities including promoter activation, cell cycle arrest at the G2/M transition and apoptosis induction. Through these activities, Vpr is thought to influence not only viral replication but also numerous host cell functions. These functions may be categorized in three groups depending on the domains of Vpr that support them: (1) functions mediated by the amino terminal portion of Vpr, like virion packaging; (2) functions mediated by the carboxyl terminal portion such as cell cycle arrest; and (3) functions that depend on central alpha-helical structures such as transcriptional activation, apoptosis and subcellular shuttling. Association of these activities to specific regions of the Vpr molecule appears to correlate to the host/viral molecules that interact with corresponding portion of Vpr. They include Gag, host transcription factors/coactivators such as SP1, the glucocorticoid receptor, p300/CREB-binding protein and TFIIB, apoptotic adenine nucleotide translocator, cyclophilin A and 14-3-3 proteins. The properties of Vpr molecule has made it difficult to assess its function and determine the true cellular interactors. Further studies on Vpr function are needed to fully assess the function of this important early regulatory molecule of HIV and other lentiviruses.