Nucleoside reverse transcriptase inhibitors (NRTIs), such as 3′-azido-3′-deoxythymidine, 2′,3′-dideoxyinosine and 2′,3′-dideoxy-3′-thiacytidine, are effective inhibitors of human immunodeficiency type 1 (HIV-1) replication. NRTIs are deoxynucleoside triphosphate analogs, but lack a free 3′-hydroxyl group. Once NRTIs are incorporated into the nascent viral DNA, in reactions catalyzed by HIV-1 reverse transcriptase (RT), further viral DNA synthesis is effectively terminated. NRTIs should therefore represent the ideal antiviral agent. Unfortunately, HIV-1 inevitably develops resistance to these inhibitors, and this resistance correlates with mutations in RT. To date, three phenotypic mechanisms have been identified or proposed to account for HIV-1 RT resistance to NRTIs. These mechanisms include alterations of RT discrimination between NRTIs and the analogous dNTP (direct effects on NRTI binding and/or incorporation), alterations in RT-template/primer interactions, which may influence subsequent NRTI incorporation, and enhanced removal of the chain-terminating residue from the 3′ end of the primer. These different resistance phenotypes seem to correlate with different sets of mutations in RT. This review discusses the relationship between HIV-1 drug resistance genotype and phenotype, in relation to our current knowledge of HIV-1 RT structure.