Calretinin is a 29-kD intracellular, vitamin D-dependent calcium binding protein that likely has multiple functional roles including intracellular calcium buffering and message targeting. This protein is a member of the EF-hand family of calcium-binding proteins and first identified in the central nervous system. It has also been identified in a wide variety of non-neural cells, both neoplastic and non-neoplastic. In the oncologic arena calretinin is most commonly used as part of a panel in the separation of pleural mesothelioma from poorly differentiated pulmonary adenocarcinomas. While in most cases highly sensitive and specific for mesothelial origin, calretinin positivity has been reported in carcinomas arising in a myriad of other tissues including ovary, testis, adrenal cortex, colon, breast, sinonasal tract, thymus, skin and even soft tissue.