Genetic resistance to African trypanosomiasis occurs in certain breeds of livestock, many species of wildlife, some strains of mice, and possibly humans. The term trypanotolerance is used to describe this trait, which in domestic livestock is best exhibited by the indigenous West African taurine breeds of cattle, N'Dama and West African Shorthorn, that have been in Africa for 5,000 to 7,000 years. Confirmation not only that these breeds are genetically resistant to trypanosomiasis but also that they are at least as productive as other indigenous breeds is currently leading to their increased use in livestock-development projects in tsetse-infested areas. Trypanotolerance appears to be related to the control of parasitemia, a capacity associated with an event that regulates parasite growth and determines how rapidly the immune response is triggered. Identification of the factors that regulate this event and definition of their genetic basis may have important implications for the development of novel strategies for control of African trypanosomiasis.