At present, a large number of immunohistochemical markers that can be used in the differential diagnosis between epithelioid peritoneal mesotheliomas and serous carcinomas are available. However, great differences of opinion exist regarding the individual value of some of these markers. This article provides a critical review of all of the information that is currently available on those markers that have the greatest potential for assisting in distinguishing between peritoneal mesotheliomas and serous carcinomas. The conclusion of this review indicates that the positive serous carcinoma markers, by and large, have a higher degree of sensitivity and specificity in assisting in discriminating between these malignancies than the positive mesothelioma markers. From a practical point of view, a combination of MOC-31 (or Ber-EP4), estrogen receptors, and calretinin immunostaining should allow a clear distinction to be made between epithelioid peritoneal mesotheliomas and serous carcinomas in most cases.