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HIV-1 polymerase, commonly known as reverse transcriptase (RT), catalyzes the critical reaction of reverse transcription by synthesizing a double-stranded DNA copy of the viral RNA genome. During the replication cycle, this synthesized DNA is integrated into the host genome. This entire process is essential for viral replication and serves as a target for several antiviral drugs. Numerous studies in biochemistry and structural biology have provided a better understanding of the function of HIV-1 RT. However, the discovery of epitranscriptomic marks, such as 2′-O-methylations on the HIV-1 RNA genome, raises questions about RT’s ability to copy RNAs adorned with these biochemical modifications. This review focuses on the significance of RT in the viral cycle, its structure and function, and the impact of 2′-O-methylations on its activity and the regulation of replication, particularly in quiescent cells.