The immunohistochemical diagnosis of mesothelioma is perhaps one of the most perplexing and controversial issues in surgical pathology. A tumor that in essence is extremely rare has managed to captivate the attention not only of pulmonologists and thoracic surgeons but also of pathologists. Throughout its history, mesothelioma has emerged as one of the tumors that has evaded definitive characterization; hence, the numerous attempts at trying to establish not only histological criteria but also histochemical, immunohistochemical, and ultrastructural guidelines for its diagnosis. Perhaps as we enter an era of more sophisticated technology, molecular biology will have an opportunity to make inroads into the diagnosis and characterization of this peculiar neoplasm. Despite the many difficulties involved in the diagnosis of malignant mesothelioma, we have recently gained significant knowledge of this entity in many respects, several decades after its description. From a morphological point of view, several variations of the histological appearances that these tumors may exhibit have been described. Traditional histochemistry and electron microscopy continue to play an important role in the evaluation of these neoplasms, with ultrastructural analysis in particular representing the most reliable technique for making this diagnosis in equivocal cases. However, because of its speed, cost-effectiveness, and general availability, immunohistochemistry has emerged as the most commonly used procedure for the diagnosis of mesotheliomas. We herein present a review of the current status of immunohistochemical evaluation of malignant lesions that are suspected of having a mesothelial lineage.