Trypanosomes are digenetic protozoans that infect domestic and wild animals, as well as humans. They cause important medical and veterinary diseases, making them a major public health concern. There are many species of trypanosomes that infect virtually all vertebrate taxa. They typically cycle between insect or leech vectors and vertebrate hosts, and they undergo biochemical and morphological changes in the process. Trypanosomes have received much attention in the last 4 decades because of the diseases they cause and their remarkable armamentarium of immune evasion mechanisms. The completed genome sequences of trypanosomes have revealed an extensive array of molecules that contribute to various immune evasion mechanisms. The different species interact uniquely with their vertebrate hosts with a wide range of evasion strategies and some of the most fascinating immune evasion mechanisms, including antigenic variation that was first described in the trypanosomes. This review focuses on the variety of strategies that these parasites have evolved to evade or modulate immunity of endothermic and ectothermic vertebrates.