The simplicity of the HIV-1 genome renders replication of this virus dependent upon host cell machinery. Similarly, pathology associated with HIV-1 infection results from interaction among cellular factors and the nine HIV-1 genes. Using genetic, biochemical, and bioinformatic techniques we identify host cell factors that contribute to HIV-1 replication, pathogenesis, and immunity. In the process we exploit HIV-1, using the virus as a probe of cellular function, with the goal of answering fundamental biological questions. By shedding light on mechanisms of HIV-1 replication and immune system evasion we contribute in the most profound way to the development of drugs and vaccines that target HIV-1 and other viruses, as well as other disease states.