Human African trypanosomiasis (HAT) is a major health concern in sub-Saharan Africa and is caused by the subspecies of Trypanosoma brucei. This protozoan parasite relies on a limited repertoire of cysteine cathepsins for growth and replication in the mammalian host. The essentiality and lack of redundancy within this protease family in T.brucei makes it a promising point for therapeutic intervention. Recent genetic studies have validated the trypanosomal cathepsin TbcatB as essential for survival in vivo, and we have developed a series of over 100 inhibitors targeted to TbcatB based on the thiosemicarbazone and purine nitrile scaffolds. This approach has yielded several potent trypanocides with excellent selectivity relative to a panel of mammalian cell lines. In addition, we have developed inhibitors with good selectivity for TbcatB relative to both trypanosomal and mammalian homologues by utilizing structure based approaches. These biochemical and cellular inhibitor studies confirm that TbcatB is an essential target in T.brucei, and that targeting this protease is a promising therapeutic strategy.