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Leishmania spp. and Trypanosoma cruzi are parasites belonging to the Trypanosomatidae family and the causative agents for two very important neglected tropical diseases (NTDs), namely leishmaniasis and trypanosomiasis, respectively. Together, they affect millions of people worldwide and the number of cases is constantly rising; thus, further effort on identifying and developing non-toxic, affordable and effective new drug is urgently needed to overcome this alarming situation. Exploring natural products from fungal and bacterial origin remains hitherto a valuable approach to find new hits and candidates for the development of new drugs against these protozoal human infections. Endophytes, which are microorganisms (fungal and bacterial) inhabiting plant tissues, represent a promising source, as they hold potential to produce a high number of distinct chemical scaffolds. These structurally diverse natural products have previously been successfully tested against a wide range of pathogenic microorganisms. The present review provides an update of endophytic compounds exerting anti-trypanosomal and anti-leishmanial effects and their predicted pharmacokinetic properties. [ABSTRACT FROM AUTHOR]