A global AIDS epidemics caused by human immunodeficiency virus type 1 (HIV-1), involving more than 2 million newly infected people annually, has existed for more than 25 years. The major obstacle in combating the global epidemic is rapid evolution of the virus by the selection of drug resistance mutations. Selection of drug-resistant HIV variants is so rapid that drug resistance is known for all of the approved anti-AIDS drugs. The review summarizes the scientific achievements in the field of reverse transcriptase drug resistance to licensed antiviral drugs, such as nucleoside (NRTI) and nonnucleoside (NNRTI) inhibitors. Principal mechanisms of their antiviral action, major drug resistance mutations, and molecular aspects of the classic mechanisms of HIV resistance to NRTIs and NNRTIs are described. The role of RNase H activity, which was recently implicated in drug resistance to reverse transcriptase inhibitors, is a focus of detailed discussion. A new NRTI and NNRTI dual resistance mechanism associated with reverse transcriptase mutations in the C-terminal region, which includes RNase H and connection domains, is analyzed. Comprehensive analysis of the factors affecting HIV drug resistance is important for understanding the molecular mechanisms of resistance and improving drug design and anti-HIV therapy.