The development of reduced susceptibility to zidovudine (AZT) has been documented in isolates of human immunodeficiency virus (HIV) from patients receiving prolonged therapy with the drug. Resistance emerges more quickly and to a higher degree in patients in later stages of disease. Progressive stepwise reductions in susceptibility occur with sequential isolates in conjunction with the cumulative acquisition of mutations in the gene for reverse transcriptase. Cross resistance to other compounds has been observed to date only with nucleosides possessing a 3'-azido moiety. The clinical significance of reduced drug susceptibility and strategies to deal with this issue are under investigation.