Trypanosomatid parasites infect over 21 million people worldwide, with a range of disease phenotypes. Trypanosoma cruzi causes American trypanosomiasis, wherein 30-40% of infected individuals develop disease manifestations, most commonly cardiomyopathy but also digestive megasyndromes. In the case of Trypanosoma brucei, the etiological agent of African trypanosomiasis, disease progression can be rapid or slow, with early or late central nervous system involvement. Finally, Leishmania species cause leishmaniasis, a disease that ranges from self-healing but scarring cutaneous lesions to fatal visceral leishmaniasis in which parasites disseminate to the liver, spleen, and bone marrow. This review highlights parasite factors involved in disease phenotype in all three trypanosomatid diseases, with a particular focus on recent advances using large-scale 'omics' techniques.