The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL-1, PRL-2, and PRL-3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Individual PRLs are overexpressed in a variety of cancer cell lines and tissues when compared with their normal counterparts. More importantly, several recent studies have shown that PRL-3 is expressed at higher levels and at a greater frequency in colorectal cancer metastases compared with primary colorectal tumors and normal colon tissue. Ectopic expression of PRLs in nontumorigenic cells can influence proliferation and the migratory and invasive properties of cells, while knockdown of endogenous PRL-3 or PRL-1 in cancerous cells using small interfering RNA can abrogate cell motility and ability to metastasize in a mouse model. However, the exact biological function and cellular substrates of the PRLs remain unclear. This review will discuss what is known about the PRLs, what makes the PRLs possible attractive targets for therapeutic intervention, and the possible future directions in PRL biology and inhibitor identification.