Our work has demonstrated that there are extensive similarities between fungal infections in mammals and non-vertebrate models including nematode and insect hosts. Host innate immune responses are also broadly conserved across many phyla and many of the virulence factors required for pathogenicity in mammals are also important for fungal survival during interactions with non-vertebrate hosts, suggesting that fungal virulence may have evolved, and been maintained, as a countermeasure to environmental predation by amoebae and nematodes and other small non-vertebrates that feed on microorganisms. Within this context, a number of virulence traits that are involved in mammalian infection from a variety of fungal pathogens are associated with C. elegans disease. C. elegans assays can be used to study microbial pathogenesis, compounds with antifungal efficacy and multidrug resistance (MDR) mechanisms. Moreover, C. elegans can be used to study fungal pathogenesis in a genome-wide scale and perform whole-animal, high throughput bioassays for novel antifungal compounds. This screening model permits data-driven decisions regarding the quality of a hit and eliminates preconceived biases about certain chemical classes or motifs. In summary, our work on the study of the interactions between invertebrate model hosts and pathogenic fungi provides insights into the mechanisms underlying pathogen virulence and host immunity, and complements the use of mammalian models by enabling whole-animal high throughput infection assays. Taken in their totality, our results indicate that a common, fundamental set of molecular mechanisms is employed by microbial pathogens against a widely divergent array of metazoan hosts.