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Trypanosomatids are unicellular protozoans of medical and economical relevance since they are the etiologic agents of infectious diseases in humans as well as livestock. Whereas  Trypanosoma cruzi  and different species of  Leishmania  are obligate intracellular parasites,  Trypanosoma brucei  and other trypanosomatids develop extracellularly throughout their entire life cycle. After their genomes have been sequenced, various comparative genomic studies aimed at identifying sequences involved with host cell invasion and intracellular survival have been described. However, for only a handful of genes, most of them present exclusively in the  T. cruzi  or  Leishmania  genomes, has there been any experimental evidence associating them with intracellular parasitism. With the increasing number of published complete genome sequences of members of the trypanosomatid family, including not only different  Trypanosoma  and  Leishmania  strains and subspecies but also trypanosomatids that do not infect humans or other mammals, we may now be able to contemplate a slightly better picture regarding the specific set of parasite factors that defines each organism's mode of living and the associated disease phenotypes. Here, we review the studies concerning  T. cruzi  and  Leishmania  genes that have been implicated with cell invasion and intracellular parasitism and also summarize the wealth of new information regarding the mode of living of intracellular parasites that is resulting from comparative genome studies that are based on increasingly larger trypanosomatid genome datasets.

Unveiling the Intracellular Survival Gene Kit of Trypanosomatid Parasites