Salivarian trypanosomes are extracellular parasites affecting humans, livestock and game animals. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are human infective sub-species of T. brucei causing human African trypanosomiasis (HAT-sleeping sickness). The related T. b. brucei parasite lacks the resistance to survive in human serum, and only inflicts animal infections. Animal trypanosomiasis (AT) is not restricted to Africa, but is present on all continents. T. congolense and T. vivax are the most widespread pathogenic trypanosomes in sub-Saharan Africa. Through mechanical transmission, T. vivax has also been introduced into South America. T. evansi is a unique animal trypanosome that is found in vast territories around the world and can cause atypical human trypanosomiasis (aHT). All salivarian trypanosomes are well adapted to survival inside the host's immune system. This is not a hostile environment for these parasites, but the place where they thrive. Here we provide an overview of the latest insights into the host-parasite interaction and the unique survival strategies that allow trypanosomes to outsmart the immune system. In addition, we review new developments in treatment and diagnosis as well as the issues that have hampered the development of field-applicable anti-trypanosome vaccines for the implementation of sustainable disease control.