African animal trypanosomosis, transmitted by tsetse flies (Glossina spp.) is a major constraint limiting the optimal utilization of land for agricultural production in tsetse-infested areas of Ghana. In the last 50 years various workers have made attempts at mapping the distribution of tsetse flies and the disease they transmit with a view to instituting appropriate control measures. Due to the increasing human population and agricultural expansion, there has been a retreat of the morsitans group of tsetse flies into protected areas. From the standpoint of livestock production, therefore, members of the palpalis group remain the most important vectors of trypanosomosis as they are able to persist even in areas of intense land use. The optimal exploitation of trypanotolerance as a means of trypanosomoses control is hampered by increased crossbreeding with trypanosusceptible breeds. Although the incidence of sleeping sickness has decreased drastically over the last decades, the current status of the disease has not been investigated. This paper takes a retrospective look at the problem of tsetse and trypanosomosis in Ghana, assesses the current disease situation and highlights some research perspectives that are relevant to the sustainable control of the disease.