Diffuse malignant mesothelioma (DMM) is an uncommon cancer with great clinical significance because it currently remains an incurable disease, and most patients die within months after diagnosis. Although DMM incidence is leveling off or decreasing in developed countries because of the strict control of asbestos use, it is increasing in countries without adequate asbestos control. In some settings, benign, reactive mesothelial hyperplasias and organizing pleuritis can be difficult to differentiate from DMM and vice versa, and the variety of DMM's histopathologic features generates an extensive list of differential diagnoses with other malignancies, particularly, metastatic malignancies, which are more frequent in the pleura than are primary malignancies. These two issues are the topic of discussion in this review, along with a brief presentation of a case of DMM that presented in a 66-year-old man with recurrent, right pleural effusions, and in whom, diagnosis of DMM had not been suspected clinically, radiographically, surgically, grossly, or initially, on frozen section. It was not until focal invasion into the skeletal muscle was discovered on permanent sections that a diagnosis of DMM could be established.