Glucosyl transferases and other trichothecene detoxification enzymes are promising tools in efforts to control Fusarium head blight (FHB) because they can reduce both the crop disease and contamination of grain with the mycotoxin deoxynivalenol (DON). Knowledge of DON and structurally related trichothecene analogs has potential to enhance utilization of the enzymes. Trichothecenes are a family of toxic secondary metabolites that are produced by species of at least 10 fungal genera with diverse ecologies. Some of the fungi, such as the FHB fungus F. graminearum, are plant pathogens, others are insect pathogens, and still others are saprotrophs. Thus, trichothecenes are produced in varied habitats where they likely function in interactions between diverse organisms. Although approximately 200 trichothecene analogs have been described, individual fungal strains tend to produce only one or a few analogs as final products of trichothecene biosynthesis. All trichothecene analogs share a core chemical structure but differ from one another by the pattern of chemical groups attached to various positions of the core structure. The existence of 200 trichothecene analogs raises the question, what drives trichothecene structural diversity. The role of DON in pathogenesis of F. graminearum combined with activities of trichothecene detoxification enzymes provide a potential answer. That is, substrate specificity of trichothecene detoxification enzymes likely drives trichothecene structural diversity. This idea is supported by findings of multiple studies. For example, Michlmayr et al. (2018 Toxins 10:111) found marked variation in activities of glucosyl transferases from barley, rice and Brachypodium against the trichothecene analogs DON, nivalenol and T-2 toxin. These and other findings suggest that when a trichothecene-producing fungus encounters a trichothecene detoxification enzyme, adaptations that result in production of structurally novel trichothecene analogs allow the fungus to elude the detoxifying effects of the enzyme. This scenario is reminiscent of gene-for-gene relationships that occur in some plant-parasite interactions. Therefore, when deploying trichothecene detoxification enzymes to combat FHB, incorporation of broad substrate specificity has potential to improve resilience of the enzymes to adaptations in Fusarium.