It has generally been considered that protein phosphatases have more diverse catalytic domain structures and mechanisms than protein kinases; however, gene annotation efforts following the human genome project appeared to have completed the whole array of protein phosphatases. Ser/Thr phosphatases are divided into three subfamilies that have different structures from each other, whereas Tyr phosphatases and dual-specificity phosphatases targeting Tyr, Ser and Thr belong to a single large family based on their common structural features. Several years of research have revealed, however, the existence of unexpected proteins, designated here as "atypical protein phosphatases", that have structural and enzymatic features different from those of the known protein phosphatases and are involved in important biological processes. In this review, we focus on the identification and functional characterization of atypical protein phosphatases, represented by eyes absent (EYA), suppressor of T-cell receptor signaling (Sts) and phosphoglycerate mutase family member 5 (PGAM5) and discuss their biological significance in cellular signaling.