The reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) is an RNA- and DNAdependent DNA polymerase capable of copying the viral genome before it gets integrated into the human host DNA. Hence, HIV-1 RT plays a major role in viral replication and represents a key target for anti-AIDS treatments. Amongst the eleven licensed drugs that inhibit RT, eight are chain-terminating nucleoside analogues (NRTIs) that compete with their natural counterparts during the DNA polymerization process. Unfortunately, under therapeutic pressure, the HIV-1 inevitably develops resistance to these inhibitors by accumulating mutations in the viral pol gene encoding RT. Mechanisms for this resistance can be sorted in two categories, depending on the nature of the drug and the selected mutations. The first category includes mutations involving a specific alteration of the discrimination between natural nucleotides and NRTIs. The second category includes mutations able to promote the removal of the incorporated NRTI and thus repair the nascent DNA chain. This review summarizes the modes of inhibition of HIV-1 RT with NRTIs, and describes the mechanisms of resistance to these drugs, based on enzymatic data correlated to crystal structures and molecular models involving HIV-1 RT. We also give insights into different aspects of resistance such as antagonistic mutations, replication capacity, and the implications for a rational, structure-based drug design.