Drug resistance in African trypanosomes has been studied for almost a hundred years. Beginning with Paul Ehrlich's work that led to the chemoreceptor hypothesis, reduction of net drug uptake has emerged as the most frequent cause of resistance. This review, therefore, focuses on trypanosomal drug transporter genes. TbAT1 encodes purine permease P2, which mediates influx of melarsoprol and diamidines. Disruption of TbAT1 in Trypanosoma brucei reduced sensitivity to these trypanocides. TbMRPA encodes a putative trypanothione-conjugate efflux pump, and overexpression of TbMRPA in T. brucei causes melarsoprol resistance. It will be important to determine the role of TbAT1 and TbMRPA in sleeping sickness treatment failures.