In the early 21st century the majority of sleeping sickness cases occurred in the Democratic Republic of the Congo (DRC), which reported about 1,000 new cases each year. By 2015, with the exception of the DRC, most other African countries had reported fewer than 100 cases annually, and many others had not reported a case in more than a decade. The dramatic decline in sleeping sickness cases was attributed to intensive control efforts, which included the isolation and proper treatment of all infected persons (including large numbers of asymptomatic chronic carriers) and the protection of humans from bites of tsetse flies by using insecticides and by maintaining extensive clearings around villages and residence compounds. Regular screening of communities in areas where tsetse flies are endemic and the culling of wild animal reservoirs, as well as personal approaches such as the use of insect repellent and the wearing of long-sleeved shirts and pants, have also helped reduce the number of cases of sleeping sickness.

Historically, epidemics of West African sleeping sickness were controlled in part through the administration of prophylactic doses of pentamidine to village populations. The destruction of wild animals that served as host reservoirs for the parasites was also carried out, particularly in East Africa; the approach helped reduce tsetse fly populations, though neither the flies nor the disease were successfully exterminated.