<p>Histone modifications regulate vital pathogenic features necessary for opportunistic fungi to cause disease. More specifically, histone modification via acetylation and methylation are two major ways that fungi regulate their growth, replication, and ability to respond to stress. This is critically important, as these genes can be potential targets for drug therapies in these difficult-to-treat pathogens. For fungi to rapidly respond to changes in their environment, they must quickly and efficiently adapt to their surroundings. Epigenetic control mechanisms, such as histone modification, allow the fungus to adapt to conditions without altering its DNA. As in other eukaryotes, fungal DNA is tightly packaged into an organized complex known as chromatin and wound around histone proteins. As these histones are modified by methylation or acetylation, specific sections of DNA can become accessible to transcriptional machinery. These histone modifications may interact with various other proteins to accomplish their functions, as well. In this way, histone modifications allow microorganisms to rapidly modify gene expression and respond to their environment. In this review, histone modifications via methylation, demethylation, acetylation, and deacetylation for select model and pathogenic fungal species are summarized concerning how they affect growth, stress response, and gene expression, as applicable. Additionally, the roles of epigenetic regulation in virulence factor expression, toxin formation, and disease are explored. Lastly, current knowledge pertaining to novel drugs and drug targets related to histone acetylation, deacetylation, and demethylation is discussed. Understanding the diverse roles of epigenetic regulation in fungal disease is a crucial first step in exploiting this critical linchpin for novel antifungal treatments of these important human pathogens.</p>