Human cryptococcosis is most commonly due to infection with Cryptococcus neoformans and C. gattii, with C. neoformans var. grubii (serotype A) accounting for the great majority of infections worldwide. Cryptococcosis is uncommon in hematopoietic stem cell transplantation; in a large multicenter study in the United States, only 2 of 306 cases were associated with hematopoietic stem cell transplantation, and 54 with solid organ transplantation (SOT). Any condition associated with prolonged or high-dose corticosteroid exposure predisposes to cryptococcosis. Other than malignancy and organ transplantation, such conditions include connective tissue disorders (e.g., systemic lupus erythematosus and vasculitides), chronic obstructive pulmonary disease, and sarcoidosis. Visual loss is one of the most serious, debilitating sequelae (if not the most serious) of central nervous system (CNS) cryptococcosis. Rapid diagnosis and treatment is the key to achieving good outcomes. Molecular tests can distinguish between C. neoformans and C. gattii but are seldom required for diagnosis of cryptococcosis due to either species. A decrease in susceptibility to azole drugs, especially fluconazole, was noted among isolates of C. neoformans var. grubii from patients with AIDS, in parallel with widespread use of fluconazole prior to the advent of highly active antiretroviral therapy (HAART). The major determinants of outcome include neurological status, intracranial pressure (ICP), the presence of cerebral mass lesions, and cryptococcal load at presentation.