Cryptococcus is a unique environmental fungus. Among the more than three dozen species of Cryptococcus, only C. neoformans and C. gattii commonly cause disease. Although many of these infections occur in immunocompromised patients, C. gattii has recently come to public attention because of an outbreak of devastating illness in immunocompetent individuals. The polysaccharide capsule of Cryptococcus is a major virulence factor, and in addition to surrounding the organism, it is also released into the environment. Cryptococcus is believed to enter the body through the lung causing pulmonary disease, but because of its neurotropic nature, the central nervous system is a major target organ. The major risk factors include HIV and organ transplantation. Depending on the site of infection and the patient's immune status, the clinical manifestations vary from asymptomatic to severe life-threatening disease. Treatment regimens depend on the immune status of the patient and the severity of the disease, and include both polyene and imidazole antifungal agents in addition to surgical adjuvant therapy. However, despite antifungal therapy, the mortality remains between 10 and 25% in patients with AIDS, and at least one-third of patients with cryptococcal meningitis experience mycological or clinical failure. Consequently, the mechanism of cryptococcal invasion, immune response, pathogenesis, and treatment continue to be areas of active study. With our advancing knowledge in these areas, we aim at better management for this devastating group of infections.