HIV-associated nephropathy (HIVAN) is a unique form of collapsing focal segmental glomerulosclerosis that typically occurs in patients with advanced HIV disease. The pathogenesis of HIVAN involves direct HIV infection and gene expression in tubular and glomerular epithelial cells; in effect, HIVAN can be considered a natural illustration of gene delivery to the kidney. HIV infection or expression of HIV genes results in dysregulation of tubular and glomerular epithelial cells and induction of local inflammatory cascades. Specific HIV genes, in particular Nef and Vpr, play prominent and synergistic roles in the pathogenesis of HIVAN, while other viral genes are not required for the development of HIVAN. The disproportionate burden of HIVAN and HIV-related end-stage renal disease in blacks suggests that host genetic factors are also important in the pathogenesis of HIVAN. Preliminary genetic studies in the mouse model have identified a potential genetic susceptibility locus, and a number of host genes are differentially expressed in the setting of HIVAN or HIV infection. The current management of HIVAN couples antiretroviral therapy with adjunctive agents that target downstream effects of HIV gene expression in the kidney. Future therapies could also target different steps in the pathogenesis of HIVAN, including viral replication, epithelial cell entry and viral gene expression, and downstream cellular pathways.