Parasitic trypanosomatids cause important diseases. Dissecting the biochemistry of these organisms offers a means of discovering targets against which inhibitors may be designed and developed as drugs. The pentose phosphate pathway is a key route of glucose metabolism in most organisms, providing NADPH for use as a cellular reductant and various carbohydrate intermediates used in cellular metabolism. The pathway and its enzymes have been studied in Trypanosoma brucei, Trypanosoma cruzi, and various Leishmania species. Its functions in these parasites are becoming clear. Some enzymes of the pathway are essential to the parasites and have structural features distinguishing them from their mammalian counterparts, and this has stimulated several programs of inhibitor discovery with a view to targeting the pathway with new drugs.