Fungal diseases represent a significant and growing threat to human health, particularly since the AIDS pandemic and increasing use of immunosuppressive drugs has produced a massive population of people with impaired immunity who are vulnerable to fungal infections. A great challenge in medical mycology is to understand how fungal virulence evolves. The vast majority of fungal species are not human pathogens and, for those that are, virulence appears to have evolved independently on many different occasions. Identifying the step(s) that convert an environmental fungus into a human pathogen, as well as subsequent changes in virulence within a pathogenic lineage, is therefore of fundamental importance. Based on a number of lines of evidence, I hypothesise that a critical regulator of fungal virulence in animal hosts is the activity of the fungal mitochondrion, an energy-generating organelle present in almost all eukaryotes. I propose to test this hypothesis comprehensively by combining genetic and cell biological approaches with high-resolution imaging methods.