Around the world, trypanosomatids are known for being etiological agents of several highly disabling and often fatal diseases like Chagas disease (Trypanosoma cruzi), leishmaniasis (Leishmania spp.), and African trypanosomiasis (Trypanosoma brucei). Throughout their life cycle, they must cope with diverse environmental conditions, and the mechanisms involved in these processes are crucial for their survival. In this review, we describe the role of heme in several essential metabolic pathways of these protozoans. Notwithstanding trypanosomatids lack of the complete heme biosynthetic pathway, we focus our discussion in the metabolic role played for important heme-proteins, like cytochromes. Although several genes for different types of cytochromes, involved in mitochondrial respiration, polyunsaturated fatty acid metabolism, and sterol biosynthesis, are annotated at the Tritryp Genome Project, the encoded proteins have not yet been deeply studied. We pointed our attention into relevant aspects of these protein functions that are amenable to be considered for rational design of trypanocidal agents. 1. Introduction Trypanosomes are parasitic protists that cause significant human and animal diseases worldwide [1], among which it is important to highlight the species relevant for human health, such as sleeping sickness or African trypanosomiasis (Trypanosoma brucei), Chagas’ disease or American trypanosomiasis (Trypanosoma cruzi), and leishmaniasis (Leishmania spp.). The life cycle of these trypanosomatids is complex, presenting several developmental stages in different hosts. They have developed a digenetic life cycle with one or several vertebrate hosts and a hematophage insect vector that allows the transmission between them. A direct consequence is the environmental changes suffered among their life cycle thus, they have to adapt their metabolism to different nutrient availability [2]. Another feature of these parasites is the presence of nutritional requirements for several essential cofactors where heme is included. They totally or partially lack the heme biosynthetic pathway (revisited by Ko？eny et al. [3]). Heme plays a fundamental role in many cellular processes. It is an essential cofactor for proteins involved in oxygen transport and storage (hemoglobin and myoglobin), mitochondrial electron transport (Complex II–IV), drug and steroid metabolism (cytochromes), signal transduction (nitric oxide synthases, soluble guanylate cyclases), and transcription and regulation of antioxidant-defense enzymes. Heme is also a regulatory molecule; its cytosolic to
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