Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in the HIV-1-seropositive population. HIVAN, which is characterized by heavy proteinuria and a rapid decline in renal function, is caused by infection and subsequent expression of viral genes in renal epithelial cells, although the exact mechanism of viral entry into these cells is unknown. The infected renal epithelium is a distinct compartment that supports the evolution of viral strains that may diverge from those found in the patient's blood. Research using animal models and in vitro studies has shown that vpr and nef are the HIV-1 genes most responsible for inducing the characteristic clinical and histopathologic syndrome of HIVAN. Dysregulation of several host factors, including mediators of inflammation, apoptosis, proliferation, transcription, and cell-cell interactions, are also critical factors in determining whether infection of the renal epithelium will lead to HIVAN. Additional research is required to delineate the mechanisms of HIVAN pathogenesis further so that more effective interventions can be implemented to prevent and treat this disease.