It is often difficult to make a firm diagnosis of mesothelioma by routine light microscopy. Most mesotheliomas are pleural and epithelial, and the problem is usually to rule out the possibility of an adenocarcinoma that has extended to the pleura from the underlying lung or a more distant source. Histochemical stains are of limited value in resolving this differential diagnosis, and the customary approach is to request a battery of immunohistochemical stains or, if tissue is available, to resort to electron microscopy. In this article, we review the abilities of the two techniques to discriminate between epithelial pleural mesothelioma and adenocarcinoma. We suggest that while there is no consistently reliable method, a carefully selected and cautiously interpreted group of immunostains will often strongly favor one or other tumor. The contribution of electron microscopy ranges from establishing a definite diagnosis in the majority of instances to offering no aid in the case of some poorly differentiated tumors.