High viral burden and replication persist during all phases of human immunodeficiency virus (HIV) disease. Although monotherapy has yielded considerable benefits, these benefits are neither absolute nor durable. Combination therapy has multiple goals: to reduce viral replication and burden; to relieve drug toxicity; to attenuate viral mutations leading to resistance and possibly to conversion from non-syncytium-inducing to syncytium-inducing virus; and to broaden the spectrum of specific cells and tissues in which antiretroviral agents are active. At present, zidovudine remains the cornerstone of antiretroviral monotherapy and combination therapy. A partial list of agents tried in combinations with and without zidovudine includes the nucleoside analogues zalcitabine and didanosine; non-nucleoside reverse-transcriptase inhibitors (nevirapine, delavirdine, atevirdine, pyridinones, TIBO derivatives); protease inhibitors; inhibitors of viral regulatory functions (tat inhibitors); cytokine antagonists; acyclovir; and colony-stimulating factors. The rationales, the regimens, and the results all vary. We usually recommend combination therapy for treatment-naive patients who are asymptomatic with < 200 CD4+ cells/mm3 or who are symptomatic, and for patients who have been receiving zidovudine monotherapy and who are stable but whose CD4+ counts have fallen to < 300 cells/mm3, or who are progressing. In the absence of definitive results from clinical trials of combination therapy, the decision to embark on this route remains to be made between each individual patient and the practitioner.