Recent research on human and crop fungal pathogens has highlighted a set of unexpected and seemingly unrelated mechanisms fuelling adaptation to drugs and the host immune system. These mechanisms include the loss of RNA interference (RNAi) in human pathogens, the rapid accumulation of point mutations, and the activity of transposable elements. Despite mechanistic differences driving the extreme accumulation of mutations (i.e., hypermutation) in some pathogens, we argue that the origins follow defined principles. The appearance of hypermutation phenotypes puts pathogens on a unique evolutionary trajectory, and mitigation strategies need to be carefully adapted.