The essential role of reverse transcription in the HIV life cycle is illustrated by the fact that half of the ∼30 FDA-approved drugs for HIV treatment target HIV-1 reverse transcriptase (RT). Even though more than 160 structures of RT deposited in the Protein Data Bank (PDB) have revealed the molecular architecture of RT in great detail, some key states of RT function and inhibition remain still unknown. Recent structures of RT initiation complexes, RT poised for RNA hydrolysis, and RT with approved drugs and investigational compounds have provided a deeper understanding of RT function and inhibition, suggesting novel avenues for targeting this central enzyme of HIV.