SUMMARYAdvances in modern medical therapies for many previously intractable human diseases have improved patient outcomes. However, successful disease treatment outcomes are often prevented due to invasive fungal infections caused by the environmental mold . As contemporary antifungal therapies have not experienced the same robust advances as other medical therapies, defining mechanisms of disease initiation and progression remains a critical research priority. To this end, the World Health Organization recently identified as a research priority human fungal pathogen and the Centers for Disease Control has highlighted the emergence of triazole-resistant isolates. The expansion in the diversity of host populations susceptible to aspergillosis and the complex and dynamic genotypic and phenotypic diversity call for a reinvigorated assessment of aspergillosis pathobiological and drug-susceptibility mechanisms. Here, we summarize recent advancements in the field and discuss challenges in our understanding of heterogeneity and its pathogenesis in diverse host populations.