An accurate diagnosis is essential to a rational approach to the treatment of diffuse malignant pleural mesothelioma and generally requires pathological examination with the application of special techniques. In recent years, immunohistochemistry has greatly abetted the distinction of mesothelioma from its many morphological mimics, yet diagnostic difficulties still remain because reactive hyperplasias and diverse tumors closely mimic mesothelioma. Mesotheliomas are classified into epithelial, mixed, sarcomatoid and undifferentiated types, based on conventional histological examination. The classification provides important prognostic information. Furthermore, differential diagnosis is directly related to histological type. Although such special techniques as histochemistry and electron microscopy continue to play an important role in some cases, immunohistochemistry often has replaced these in distinguishing epithelial-type mesothelioma from metastatic adenocarcinoma. It is also helpful in distinguishing sarcomatoid mesothelioma from it numerous morphological mimics. The distinction of mesothelioma from reactive mesothelial proliferations is still based on morphological examination and may be quite problematic. Recent cytogenetic studies, which have identified characteristic clonal deletions in mesotheliomas, give promise of providing valuable assistance in this distinction in the future.