Cryptococcal disease is the most common life-threatening fungal infection in patients with AIDS. The most common manifestation, meningitis, has an indolent presentation that may lead to a delay in diagnosis. Although clinical trials have demonstrated efficacy with fluconazole in some patients, amphotericin B, with or without flucytosine, is the treatment of choice. Lifelong suppression of cryptococcal disease after initial therapy, however, is best achieved with fluconazole. Prognostic staging systems and primary prophylaxis of cryptococcal disease are also discussed.