Programmed cell death (PCD) is a biochemical process that plays an essential role in the development of multicellular organisms. However, accumulating evidence indicates that PCD is also present in single-celled eukaryotes. Thus, trypanosomatids might be endowed with a PCD mechanism that is derived from ancestral death machinery. PCD in trypanosomatids could be a process without a defined function, inherited through eukaryotic cell evolution, which might be triggered in response to diverse stimuli and stress conditions. However, recent observations suggest that PCD might be used by trypanosomatids to maximize their biological fitness. Therefore, PCD could represent a potential pharmacological target for protozoan control.