Tsetse control has long been an important option for reducing the impact of African trypanosomiasis but, although many effective methods have been used, the results have seldom proved sustainable. Developments to reduce cost and environmental impact increasingly limit the choices available for control and the scale of operations has declined. Conversely, human trypanosomiasis has reached epidemic proportions in some countries. Here, Reg Allsopp argues that those tasked with managing trypanosomiasis or committed to poverty alleviation in Africa should consider large-scale, area-wide tsetse control involving all proven methods, including aerial spraying and the sterile insect technique.