Resistance of human immunodeficiency virus (HIV) to available nucleoside reverse-transcriptase inhibitors, the only approved therapeutic agents for HIV infection, has been recognized since shortly after the initial trials of zidovudine. The rapid development of resistance of the virus to nonnucleoside reverse-transcriptase inhibitors has also been documented. Drs. Erice and Balfour ofthe University of Minnesota herein the current status of methods used to assay for such resistance, the possible use of combinations of antiretroviral agents to delay the development of resistance, and the potential clinical implications of a loss of susceptibility to these drugs. Resistance to zidovudine apparently is associated with immunologic deterioration; therefore, the provision of care to HIV-infected persons in the future may require an understanding of these issues.