Zidovudine-resistant strains of HIV became apparent in many patients soon after advent of zidovudine (AZT) monotherapy. While this resistance could be unequivocally correlated with multiple mutations in HIV reverse transcriptase (D67N, K70R, T215F/Y, K219Q), the mechanism or phenotype for this resistance has remained obscure for more than a decade, despite active investigation. Recent studies indicate that AZT resistance may be related to removal of chain-terminating AZT from the 3'-terminus of the primer, by a process known as pyrophosphorolysis. This process is catalyzed by HIV-1 reverse transcriptase (RT), and is the reverse reaction of DNA polymerization. The D67N/K70R mutations result in a significantly increased rate of RT-catalyzed pyrophosphorolysis at physiological levels of pyrophosphate, which leads to a decrease in the extent of AZT chain termination of nascent viral DNA. The potential replication deficit of an increased reverse reaction during DNA synthesis is compensated by increased DNA synthesis processivity, a phenotype that results from the T215F/Y/K219Q mutations in RT. The net result of these multiple phenotypes imparted by the multiple mutations in RT is the facile synthesis of full-length viral DNA in the presence of AZT. Copyright 1999 Harcourt Publishers Ltd.