Infections due to Cryptococcus species occur globally and in a wide variety of hosts, ranging from those who are severely immunosuppressed to those who have phenotypically "normal" immune systems. Approximately 1 million cases of cryptococcosis occur throughout the world, and is it estimated that there are 650,000 associated deaths annually. Most of these cases occur among patients with advanced HIV disease, but a growing number occur among solid organ transplant recipients and others receiving exogenous immunosuppression, patients with innate and acquired immunodeficiency, and otherwise immunologically normal hosts. Much of our recent knowledge is solely derived from clinical experience over the last 2 to 3 decades of cryptococcosis among HIV-infected patients. However, based on recent observations, it is clear that there are substantial differences in the epidemiology, clinical features, approaches to therapy, and outcome when comparing HIV-infected to non-HIV-infected individuals who have cryptococcosis. If one carefully examines cryptococcosis in the three largest subgroups of patients based on host immune status, specifically, those with HIV, solid organ transplant recipients, and those who are non-HIV, non-transplant (NHNT) infected persons, then one can observe very different risks for infection, varied clinical presentations, long-term complications, mortality, and approaches to therapy. This article focuses on cryptococcosis in the non-HIV-infected patient, including a brief review of ongoing events in the Pacific Northwest of the United States and Canada relative to the outbreak of Cryptococcus gattii infections among a largely immunologically normal population, and highlights some of the key insights and questions which have emerged as a result of these important new observations.