Trypanosomosis is a serious threat to both man and animals mostly in Africa. Although the first pathogenic trypanosome was discovered over a hundred years ago, there is still no prospect for effective control or eradication of the disease through the development and use of vaccines because of the phenomenon of antigenic variation. Control continues to rely heavily on chemotherapy and vector control strategies. This therapy and prophylaxis depends on the use of drugs which, apart from having been developed over 5 decades ago, suffer from such limitations as toxicity and with their continued use, drug resistance. Resistance to currently used drugs is a serious problem in most fields of anti-microbial chemotherapy, particularly in the case of trypanosomosis where resistance and cross-resistance in animals and man have been developing rapidly. The frequently and widely reported decreasing efficiency of available trypanocides, difficulties of sustaining tsetse control and little hope that a conventional, anti-trypanosome vaccine will be produced in the near future, increase the imperative need for new drugs and alternative effective ways for the control of trypanosomosis. This review examines aspects of drug resistance in pathogenic trypanosomes, measures to minimise it, areas of future research in new drug targets and alternative control strategies. Based on these, it is our opinion that for now the management and control of trypanosomosis will continue to depend on proper usage of the few available trypanocides, especially strategic deployment of the sanative drugs in order to reduce the development of drug resistance, in addition to the continued use of environmentally friendly vector control programmes such tsetse trapping.