Only four drugs are available for the chemotherapy of human African trypanosomiasis or sleeping sickness; Suramin, pentamidine, melarsoprol and eflornithine. The history of the development of these drugs is well known and documented. suramin, pentamidine and melarsoprol were developed in the first half of the last century by the then recently established methods of medicinal chemistry. Eflornithine, originally developed in the 1970s as an anti-cancer drug, became a treatment of sleeping sickness largely by accident. This review summarises the developmental processes which led to these chemotherapies from the discovery of the first bioactive lead compounds to the identification of the final drugs.