Invasive fungal infections (IFIs) occur predominantly in immunocompromised individuals but can also be seen in previously well persons. The human innate immune system recognizes key components of the fungal cell wall as foreign resulting in a myriad of signaling cascades. This triggers release of antifungal molecules as well as adaptive immune responses, which kill or at least contain the invading fungi. However, these defences may fail in hosts with primary or secondary immunodeficiencies resulting in IFIs. Knowledge of a patient's immune status enables the clinician to predict the fungal infections most likely to occur. Moreover, the occurrence of an opportunistic mycosis in a patient without known immunocompromise usually should prompt a search for an occult immune defect. A rapidly expanding number of primary and secondary immunodeficiencies associated with mycoses has been identified. An investigative approach to determining the nature of these immunodeficiencies is suggested to help guide clinicians encountering patients with IFI. Finally, promising adjunctive immunotherapy measures are currently being investigated in IFI.