Progress in chemotherapy for African trypanosomiasis, caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, is crucial for controlling this neglected tropical disease. This comprehensive overview examines the evolution of drug treatments, mechanisms of action, resistance patterns, and therapeutic efficacy in the context of African trypanosomiasis chemotherapy. Various classes of drugs, including suramin, pentamidine, melarsoprol, eflornithine, and newer agents like fexinidazole, are evaluated for their effectiveness and safety profiles. The review discusses the importance of combination therapies, pharmacokinetics, and pharmacodynamics in optimizing treatment outcomes and overcoming drug resistance. Additionally, emerging therapeutic strategies and ongoing research efforts aimed at developing novel antitrypanosomal agents are highlighted, offering insights into the future directions of chemotherapy for African trypanosomiasis.