Genetic analysis of molecular and functional traits in immune cells, such as gene and protein expression and effector functions, offers a promising strategy for investigating phenotypic variation and dissecting the molecular mechanisms underlying propensity to infection. We propose a global approach to elucidate the genetic architecture of antifungal immunity to major fungal pathogens by investigating the molecular processes of immune function at the cellular level during fungal infection and in human patients suffering from fungal disease. Our major goals include the identification of interindividual genetic variation that modulates fungal-sensing transcriptional and functional responses, the annotation of molecular and functional phenotypes whereby genetic variants control antifungal immune responses, and the dissection of the contribution of genetic variants to the development of fungal infection in human patients at risk. Using cutting-edge research tools that combine genome-wide genotyping, transcriptomic profiling, advanced cellular model systems, and studies in human patients, we propose to establish an unprecendented understanding of the genetic, molecular and biological processes that define an individual’s susceptibility to fungal disease.