The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL‐1, ‐2, ‐3; gene name PTP4A1, PTP4A2, PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer, and normal physiology, particularly emphasizing on the use of in vivo mouse models. We also highlight a novel relationship positioning PRL as a central node controlling magnesium homeostasis through an association with the CNNM proteins, which are involved in magnesium transport.