Introduction of antiretroviral therapy combining protease and reverse transcriptase (RT) inhibitors has dramatically improved the quality of life and survival of patients infected with the human immunodeficiency virus (HIV). However, effective long-term therapy of HIV-infection has been severely hampered by the development of drug resistance. Resistance to antiretroviral drugs is generally conferred by specific amino acid substitutions in the target gene of the drug. Yet, occasionally gene insertions are being observed. The most commonly observed insertion is seen during substrate analogue RT inhibitor therapy and is selected in the beta3-beta4 loop of the RT enzyme. This flexible loop is located in the fingers subdomain of the enzyme and plays an important role in substrate binding. The acquisition of drug resistance related mutations or insertions might come at a price, which is reduced performance of the enzyme resulting in a diminished replication capacity of the virus. Various types of insertions have been described, and, in this review, we have summarized these data and discussed the mechanism of action of the RT inserts and their impact on both drug susceptibility and replication capacity.