In this article, we summarize recent knowledge on drug-resistance mutations within HIV reverse transcriptase (RT). Several large-scale HIV-1 genotypic analyses have revealed that the most prevalent nucleos(t)ide analog RT inhibitor (NRTI)-resistance mutation is M184V/I followed by a series of thymidine analog-associated mutations: M41L, D67N, K70R, L210W, T215Y/F and K219Q/E. Among non-nucleoside RT inhibitor (NNRTI)-resistance mutations, K103N was frequently observed, followed by Y181C and G190A. Interestingly, V106M was identified in HIV-1 subtype C as a subtype-specific multi-NNRTI-resistance mutation. Regarding mutations in the HIV-1 RT C-terminal region, including the connection subdomain and RNase H domain, their clinical impacts are still controversial, although their effects on NRTI and NNRTI resistance have been confirmed in vitro. In HIV-2 infections, the high prevalence of the Q151M mutation associated with multi-NRTI resistance has been frequently observed.