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.