Trypanosomatids of the order Kinetoplastida are the causative agents of several lethal parasitic diseases, such as Chagas’ disease (Trypanosoma cruzi), African sleeping sickness (Trypanosoma brucei), and various leishmaniasis (Leishmania donovani, major, and tropica). Despite their epidemiological importance, the chemotherapy of trypanosomal infections is still an unsolved problem. Indeed, no vaccine or recommended drugs are currently available to prevent these diseases. Moreover, once the infections have progressed to later stages no medications have proven effective. Actually, the marketed drugs, although helpful during the acute stages, are ineffective for chronic administration and produce severe side effects due to their high toxicity. Further work from the pharmaceutical community, especially at academic level, is therefore urgently needed to discover new drugs that are not only active, but also affordable and readily available. In this review, we describe, as a case study of structure-based drug design, the development of new inhibitors of the parasitic enzyme trypanothione reductase, as potential lead compounds for the treatment of trypanosomal diseases.