Trypanosomes are protozoan parasites of medical and veterinary importance. It is well established that different species, subspecies and strains of trypanosome can cause very different disease in the mammalian host, exemplified by the two human-infective subspecies of Trypanosoma brucei that cause either acute or chronic disease. We are beginning to understand how the host response shapes the course of the disease and how genetic variation in the host can be a factor in disease severity, particularly in the mouse model, but until recently the role of parasite genetic variation that determines differential disease outcome has been a neglected area. This review will discuss the recent advances in this field, covering both our current knowledge of the T. brucei genes involved and the approaches that are leading towards the identification of T. brucei virulence genes. Finally, the potential for using parasite genotype variation to examine the evolutionary context of virulence will be discussed.