The deregulated expression of members of the phosphatase of regenerating liver (PRL) family has been implicated in the metastatic progression of multiple human cancers. Importantly, PRL‐1 and PRL‐3 both possess the capacity to drive key steps in metastatic progression. Yet, little is known about the regulation and oncogenic mechanisms of this emerging class of dual‐specificity phosphatases. This prospect article details the involvement of PRLs in the metastatic cascade, the regulatory mechanisms controlling PRL expression, and recent efforts in the characterization of PRL‐modulated pathways and substrates using biochemical and high‐throughput approaches. Current advances and future prospects in anti‐cancer therapy targeting this family are also discussed. J. Cell. Biochem. 111: 1087–1098, 2010. © 2010 Wiley‐Liss, Inc.