Large-scale clinical end point studies comparing antiretroviral therapy with zidovudine alone, didanosine alone, and zidovudine combined with didanosine indicate that both didanosine alone and zidovudine/didanosine provide a better clinical outcome than zidovudine alone in patients with human immunodeficiency virus (HIV) infection. The superiority of combination didanosine/zidovudine therapy over zidovudine monotherapy was most significant in treatment-naive patients, but benefit was also seen in patients who had previously received zidovudine and also in all stages of disease. Activity marker data from other studies suggest that double or triple combination therapies that include didanosine and nucleoside analogues other than zidovudine, non-nucleoside reverse transcriptase inhibitors or protease inhibitors result in powerful suppression of viral replication that will provide additional clinical benefits. Apart from mostly mild gastrointestinal disturbances, didanosine alone and in various combination therapies has been generally well tolerated. Thus, didanosine represents a potent, versatile nucleoside analogue with potential benefits in both current and future antiretroviral regimens for HIV infection.