Protein phosphorylation is one of the most important post-translational modifications regulating various signaling processes in all known living organisms. In the cell, protein phosphatases and protein kinases play a dynamic antagonistic role, controlling the phosphorylation state of tyrosine (Tyr), serine (Ser) and threonine (Thr) side chains of proteins. The reversible phosphorylation modulates protein function, through initiating conformational changes, which influences protein complex formation, alteration of enzyme activity and changes in protein stability and subcellular localization. These molecular changes affect signaling cascades regulating the cell cycle, differentiation, cell-cell and cell-substrate interactions, cell motility, the immune response, ion-channel and transporter activities, gene transcription, mRNA translation, and basic metabolism. In addition to these processes, in unicellular parasites, like Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp., additional signaling pathways have evolved to enable the survival of parasites in the changing environment of the vector and host organism. In recent years the genome of five trypanosomatid genomes have been sequenced and annotated allowing complete definition of the composition of the trypanosomatid phosphatomes. The very diverse environments involved in the different stages of the kinetoplastids' life cycle might have played a role to develop a set of trypanosomatid-specific phosphatases in addition to orthologues of many higher eukaryote protein phosphatases present in the kinetoplastid phosphatomes. In spite of their well-described phosphatomes, few trypanosomatid protein phosphatases have been characterized and studied in vivo. The aim of this review is to give an up to date scope of the research, which has been carried out on trypanosomatid protein phosphatases.