OBJECTIVE Antiretroviral regimens that combine nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors have consistently been the most effective regimens for the initial treatment of HIV-1 infection. Such combinations have been manufactured in several fixed-dose combinations and are the most commonly used treatments worldwide. The success of these regimens may partly be a result of the synergistic manner in which the two classes of compounds inhibit the HIV-1 reverse transcriptase enzyme. RESULTS Multiple synergistic effects have been described in the mechanisms and pathways of drug resistance. This review outlines what is currently known about the interactions between nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor resistance. CONCLUSIONS These synergistic interactions are likely to be the driving force behind the potency and durability of the nucleoside reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor combinations used in clinical practice.