Site-directed mutagenesis has demonstrated that changes within the human immunodeficiency virus reverse transcriptase coding sequence alone can account for viral resistance to inhibitors. Inhibitor sensitivity of mutant enzymes in vitro correlates with the sensitivity of the virus to non-nucleoside inhibitors observed in vivo, but this is not the case with nucleoside analogs. Recent structural, kinetic, and site-directed mutagenesis studies demonstrate the importance of enzyme-nucleic acid contacts in determining enzyme sensitivity to inhibitors in vitro, as well as how accurately the reverse transcriptase synthesizes DNA.