Purpose of the Review: Cryptococcal disease is most often thought of in the context of HIV infection. Much of our knowledge of the disease originates from its management in the HIV-positive population over the last 30 years. While the majority of cases globally continue to occur in the setting of advanced HIV, Cryptococcus species is increasingly responsible for disease in HIV-negative populations including those considered normal hosts and these HIV-negative populations will be the focus of this review. Recent Findings: Currently available data indicated that significant differences exist in epidemiology, clinical presentation, management and outcomes of cryptococcal disease in HIV-negative populations when compared to those living with HIV. Summary: Further research is required to improve our knowledge of cryptococcal disease in particular in HIV-negative cohorts so as to optimise management of the disease in the future.