Cell death is regulated by a myriad of intracellular molecular pathways, with many involving protein phosphorylation and dephosphorylation. In this review, we will focus on Ser/Thr phosphatases-mediated regulation in cell apoptosis as well as on their potential roles in cell necrosis. The emerging functional importance of Ser/Thr protein phosphatases in cell death regulation adds new dimension to the signaling mechanisms of cellular function, physiology, and diseases.