Knowledge of cell signaling pathways in trypanosomatids is crucial for the future design of new drugs to treat diseases caused by these parasites. The publication of the complete genome sequences of three pathogenic trypanosomatids, Trypanosoma brucei, T. cruzi and Leishmania major, revealed numerous protein members of signaling pathways that modulate important processes, such as cell differentiation. Even so, little is known about the role that these proteins play in the physiology of trypanosomatids. This review aims to stimulate discussion on this subject to encourage further studies of the signaling pathways involved in the cell differentiation of trypanosomatids.