The development of drug combinations that act effectively against both wild-type and mutated resistant forms of HIV-1 reverse transcriptase (RT) is a major goal in management of HIV disease. Recent studies have shown that resistance to different nucleoside analog RT inhibitors (NRTIs), an important class of anti-viral drugs, can result in different amino acid substitutions in close proximity to the dNTP binding pocket of the enzyme. Some of these mutations have been shown to cause cross- or multiple resistance among various members of this family of inhibitors. In contrast, certain combinations of amino acid substitutions can sometimes lead to increased drug susceptibility and may also result in resensitization of formerly resistant viruses. A biochemical understanding of these complex viral phenotypes may be of major importance in regard to development of novel chemotherapeutic strategies that can act at the level of drug-resistant mutated enzymes. In this review, we discuss several principles that help to explain the increased susceptibility and resensitization to some antiviral agents used in the context of combination treatment. The conclusions are largely based on our current understanding of mechanisms involved in drug-resistance to 3TC and AZT. Copyright 2000 Harcourt Publishers Ltd.