Hypersusceptibility to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) is a recently described observation in which approximately 30% of HIV isolates with resistance to nucleoside reverse transcriptase inhibitors exhibit greater phenotypic susceptibility to the NNRTI class than does wild-type HIV. This increased susceptibility has been associated with better virologic outcomes in several clinical trials and observational cohorts in which NNRTI-based regimens were used. Nucleoside mutations at positions 215, 208, and 118 are associated with efavirenz hypersusceptibility, but to date, there have been no reported biochemical or structural studies on the effect of these mutations on NNRTI binding or on binding pocket conformational changes. There is currently no basis for the practical use of NNRTI hypersusceptibility to guide HIV therapeutic strategies, but it theoretically could affect the evolution of resistance in antiretroviral-naive patients who begin NNRTIs with various nucleoside backbones.