Trypanosomes are parasitic protozoans that afflict both man and livestock in sub-Saharan Africa. The current chemotherapy of African trypanosomiasis relies on a few drugs, most of which were developed decades ago. Combinations of toxic side effects and poor efficacy of current drugs demand an urgent need for the development of novel and effective therapeutic agents. The proteasome is a multisubunit proteinase complex that plays a critical role in intracellular protein degradation. Despite being essential to all eukaryotic cells, there are significant differences between the trypanosomal and mammalian proteasomes which makes this enzyme complex a promising target for anti-trypanosomal drug development. In this review article, the structural properties, enzymatic activities and inhibitor sensitivities of the proteasomes of Trypanosoma brucei and mammalian cells are compared. In addition, the trypanocidal activities of the different classes of proteasome inhibitors are summarized.