Nucleoside reverse transcriptase inhibitors (NRTIs) comprise the first class of drug with proven antiretroviral efficacy against HIV-1, and the first in which drug resistance was reported. Ongoing research in the area of NRTI resistance and cross-resistance contributes much to what we know about the failure of antiretroviral therapy. The genetic mutation patterns responsible for resistance to the available NRTIs have been well documented. This information is being used to plan rational drug therapy. Furthermore, it serves as the standard against which to evaluate response patterns to multiple-drug regimens, ultimately enabling more accurate prediction of outcome with combination therapies. Other features of NRTI resistance, such as the theoretic reversal of zidovudine resistance associated with the M184V mutation or the powerful influence of the Q151M multiple-drug resistance mutation, have revealed the unpredictable nature of HIV resistance and how much we still need to learn. Although NRTIs are the cornerstone of antiretroviral therapy at present and are used to control disease progression for extended periods, it is clear that eventually resistance occurs with all antiretroviral regimens. Future research into NRTI-resistance mutations, mutational interactions, treatment sequencing, and viral fitness and fidelity will continue to refine our understanding of drug resistance and improve our ability to delay or eliminate resistance and advance HIV control.