The complexity and diversity of microbial colony morphologies have contributed to the identification of pathogenic microbes for decades. Even as biomarker-based approaches are adopted for diagnosis of fungal infections, culture-based methods remain valuable for the identification of specific etiological agents and determination of antifungal susceptibility [1]. Thus, when obtainable, infectious organisms are observed as macroscopic colony biofilms in clinical settings. We define macroscopic morphologies (a strain’s morphotype) as the collective phenotypes of form and/or structure attributed to a group of organisms of the same species within a defined area such as a colony. Clinical isolates of Aspergillus fumigatus, Cryptococcus neoformans, and Candida spp. have been reported for decades to be morphologically variable within and between patients [2–4]. Similarly, diverse population-level macroscopic morphologies of bacterial pathogens have been observed in clinical samples [5, 6]. A key question is whether observed microbial morphotypes tell us anything about their virulence. Below, we discuss the intrinsic and extrinsic factors that contribute to macroscopic morphological variation in fungi and bacteria. We then discuss fungal and bacterial examples linking macroscopic morphology with virulence and the challenges faced with studying this relationship. Finally, we discuss the importance of investigating recurring and distinct fungal macroscopic morphologies for furthering our understanding of host–fungal interactions.