Under most circumstances, certain breeds of domestic ruminants show a remarkable resistance to the effects of African trypanosomiasis: they can tolerate the presence of parasites while apparently controlling levels of parasitaemia and, crucially, not showing the severe anaemia and production loss that are characteristic of infection in susceptible hosts. As discussed here by Stephen Kemp and Alan Teale, the genetic control of this phenomenon might finally be yielding to gene mapping studies. Genetic regions determining susceptibility to trypanosomiasis in mice have been identified and parallel studies are well advanced in cattle. There is growing evidence that only modest numbers of genes are involved in determining the difference between a susceptible and a resistant animal. These observations raise a new series of important questions concerning the possible exploitation of major trypanotolerance genes and the way that they might function in different genetic and physical environments.