July 2021—The accurate diagnosis of malignant pleural mesothelioma is important because of its association with asbestos inhalation and because it is an aggressive tumor with poor outcome despite multimodal treatment. Unfortunately, however, diagnosing malignant pleural mesothelioma is not straightforward. Initial diagnosis often occurs on small biopsies, and the disease has morphologic overlap not only with other neoplasms that affect the lungs and pleura, such as solitary fibrous tumor or synovial sarcoma, but also with reactive conditions, such as reactive mesothelial hyperplasia or sclerosing fibrous pleuritis. While immunohistochemical markers can provide ancillary information, many of them are nonspecific and can lead to diagnostic dilemmas. Sequencing of cancer genes can help in some situations but cannot provide a definitive diagnosis.