Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS). Its management is characterized by the administration of initial combination antifungal therapy by following the principles of induction, consolidation, and maintenance therapy with aggressive management of elevated intracranial pressure (ICP). These tenets apply to patients with and without AIDS. Recent prospective trials on combination antifungal therapy, and the timing of the initiation of highly active antiretroviral therapy (HAART), suggest amphotericin B plus flucytosine and initiation of HAART are optimal therapy for management of patients with AIDS and cryptococcal meningitis. The paucity of prospective data on the management of cryptococcal meningitis in patients without AIDS is the most challenging aspect of formulating treatment guidelines, but the principles of induction, consolidation, and maintenance still apply. Combination antifungal therapy with a lipid formulation of amphotericin B plus flucytosine is generally indicated for this group, especially for those with a predisposition to renal dysfunction. Future research targeting this population may further inform recommendations. © 2010 Springer Science+Business Media, LLC.