AbstractDeciphering cellular and molecular mechanisms that maintain host immune homeostasis with fungi and the breakdown of this homeostatic tolerance during fungal infections disease is a challenge in medical mycology. In fact, the virulence of fungi may be determined by the interaction between fungi and the host immune status and its classification as a commensal microorganism or a pathogen may shift depending on the balance. In addition to the central role of the IL‐12/IFN‐γ‐dependent Th1 responses in cell‐mediated immune protection against fungi, Th17 cells provide protection and inflammation at mucosal surfaces, and Tregs fine‐tune immune responses to prevent damage to the host. Recent evidence indicates that IL‐22‐producing cells, employing primitive antifungal effector mechanisms, contribute to antifungal resistance at mucosal surfaces under conditions of defective adaptive immunity. The fact that IL‐22 production is driven by commensals points to the need of an integrated, systems biology approach to improve our understanding of the inherent and intimate mechanisms underlying multilevel host–fungus interactions.