Viral protein R (Vpr) of HIV-1 belongs to a class of so called 'accessory' proteins, originally thought to be dispensable for virus replication, at least in vitro. Indeed, viruses with mutated or deleted Vpr replicate well in transformed T cell lines. However, recently published results reveal several important functions performed by Vpr, which are critical for HIV-1 replication in vivo. Vpr plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication in non-dividing cells. Vpr also induces cell cycle arrest in proliferating cells, stimulates virus transcription, and regulates activation and apoptosis of infected cells. These diverse functions are mediated by the interaction of Vpr with different cellular proteins, many of which carry the WxxF amino acid motif. The molecular events underlying the activity of Vpr are reviewed in this article.