HIV viral protein r (Vpr) exerts a variety of cellular effects, including modulation of transcription and cytokine production, apoptosis, and cell cycle arrest. Vpr induces these affects by mechanisms that include inhibition of NFkappaB activation, inducing mitochondrial injury, and promoting proteasomal degradation of cellular factor(s) leading to cell cycle arrest. Murine models have provided invaluable contributions to our understanding of HIV pathogenesis, however many of the HIV-1 proteins, including Vpr, differ in their cellular effects depending upon cell type and speciesspecific factors. Since the majority of in vivo studies elucidating the role of Vpr in disease pathogenesis have utilized murine models, it is critical to understand the species-specific factors that may affect Vpr function. In this manuscript, we review the cellular pathways and end organ effects of Vpr that have been studied in murine cell lines and mouse models, and discuss the relevance of these studies to the role of Vpr in disease in persons living with HIV/AIDS.