Fungal diseases represent an important paradigm in immunology, since they can result from either the lack of recognition or over-activation of the inflammatory response. Current understanding of the pathophysiology underlying fungal infections and diseases highlights the multiple cell populations and cell-signaling pathways involved in these complex conditions beyond the dysregulated chaos in which fungal infection and disease are perceived. A systems biology approach that integrates investigations of immunity at the systems-level is required to generate novel insights into this complexity and to decipher the dynamics of the host-fungus interaction. Recent advances in the immune response to fungi have highlighted the cellular and molecular mechanisms of immune adaptations that maintain homeostasis with the fungal biota and its possible rupture in fungal infections and diseases. Functionally distinct modules of immunity, i.e., resistance and tolerance, evolved for the achievement of the best-fitted host-fungus interaction in mammals, are now essential components of the host-fungus interaction in the vertebrate host.