Inhalation of spores or desiccated yeasts cells of Cryptococcus neoformans or C. gattii from the environment causes natural pulmonary infection that is usually regressive and unspecific. The main virulence factors of C. neoformans/C. gattii species complexes include important phenotypic characteristics for diagnosis, such as capsule production, melanin formation, and thermotolerance The diagnosis of cryptococcosis is traditionally based on fungal isolation from clinical specimens and/or visualization of fungal cells by direct exam or histopathology of tissues with specific stains to identify the capsule or the melanin. Negative cerebrospinal fluid direct exam requires cryptococcal antigen detection, which will reliably diagnose the infection. Histopathologic identification in biopsy specimens is based on the micromorphological characteristics of Cryptococcus spp. Cryptococcosis manifests as a respiratory, disseminated, or meningeal disease. The pattern of cryptococcal pulmonary disease varies, ranging from asymptomatic to acute respiratory distress syndrome. Cryptococcal peritonitis occurs in individuals undergoing peritoneal dialysis or with hepatic cirrhosis.