Diffuse malignant mesothelioma is an uncommon, aggressive malignancy that occurs most often in the pleura of the lung. This article reviews the risk factors, incidence, signs, symptoms, diagnosis, staging, treatment options, and follow-up care of diffuse malignant pleural mesothelioma (DMPM). Curative approaches for treating DMPM are limited, and survival rates rarely exceed two years. Treatments such as surgery, chemotherapy, and radiotherapy have shown limited benefit in improving survival. Extrapleural pneumonectomy combined with multimodal treatments provides a potentially curative approach, and newer efforts in multimodality therapy are promising. Clinical trials utilizing intrapleural chemo-, photodynamic, gene, and immunotherapies currently are under way.