Resistance testing has emerged as an important tool for antiretroviral management. Research continues to refine phenotypic susceptibility cut-offs and genotypic interpretation schemes that relate resistance mutations with antiretroviral drug effectiveness. Highly sensitive phenotypic assays have allowed for the recognition of drug hypersusceptibility in HIV, and other studies have related hypersusceptibility to resistance mutations; efforts are ongoing to use what is known about hypersusceptibility to optimize the benefits of antiretroviral therapy. Resistance-associated mutations in several viral genes result in viruses that exhibit reduced replication capacity; assays to measure replication capacity are being developed that may, in the future, be useful in guiding therapy to improve treatment outcomes. This article summarizes a presentation given by Richard H. Haubrich, MD, at the International AIDS Society-USA Sacramento course in November 2003.