Life-threatening invasive fungal infections are becoming increasingly common, at least in part due to the prevalence of medical interventions resulting in immunosuppression. Opportunistic fungal pathogens of humans exploit hosts that are immunocompromised, whether by immunosuppression or genetic predisposition, with infections originating from either commensal or environmental sources. Fungal pathogens are armed with an arsenal of traits that promote pathogenesis, including the ability to survive host physiological conditions and to switch between different morphological states. Despite the profound impact of fungal pathogens on human health worldwide, diagnostic strategies remain crude and treatment options are limited, with resistance to antifungal drugs on the rise. This review will focus on the global burden of fungal infections, the reservoirs of these pathogens, the traits of opportunistic yeast that lead to pathogenesis, host genetic susceptibilities, and the challenges that must be overcome to combat antifungal drug resistance and improve clinical outcome.