Nucleoside and non-nucleoside analog inhibitors of HIV Type 1 reverse transcriptase are currently used in the clinic to treat infection with this retrovirus. Following their intracellular activation, nucleoside analogs act as chain terminators, while non-nucleoside analog reverse transcriptase inhibitors bind to a hydrophobic pocket in close proximity to the active site and inhibit the catalytic step. Compounds that belong to the two different classes of drugs are frequently administered in combination to take advantage of the different mechanisms of drug action. However, the development of drug resistance may occur under conditions of continued, residual viral replication, which is a major cause of treatment failure. This review addresses the interaction between different inhibitors and resistance-conferring mutations in the context of combination therapy with drugs that target the reverse transcriptase enzyme. Focus is placed on biochemical mechanisms and the development of future approaches.