Human African trypanosomiasis is an infectious disease which has resulted in the deaths of thousands of people in Sub-Saharan Africa. Two subspecies of the protozoan parasite Trypanosoma brucei are the causative agents of the infection, whereby T. b. gambiense leads to chronic development of the disease and T. b. rhodesiense establishes an acute form, which is fatal within months or even weeks. Current chemotherapy treatment is complex, since special drugs have to be used for the different development stages of the disease, as well as for the parasite concerned. Melarsoprol is the only approved drug for effectively treating both subspecies of human African trypanosomiasis in its advanced stage, however, the drug's potency is constrained due to an unacceptable side effect: encephalopathy, which develops in one out of every 20 patients who are treated with the drug. In addition to the deleterious treatment with melarsoprol, the number of drug-resistant strains of T. brucei supp. increases. Mechanisms of drug resistance have been elucidated and involve decreased drug import through the loss of the purine transporter P2 as well as enhanced drug export, mediated by a multidrug resistance-associated protein called TbMRPA. Thereby, the medical treatment with the available chemotherapeutics becomes exceedingly difficult. A promising strategy for research into new drugs and moreover, to overcome drug resistance, are compounds derived from natural sources. This study provides an overview of the recently discovered small molecules with trypanocidal activity against T. b. gambiense and T. b. rhodesiense. In addition, former promising compounds are touched upon.

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