This special issue of the Annals of Translational Medicine details an in-depth description of the most relevant topics on malignant pleural mesothelioma (MPM). The discussions include fascinating discoveries that deepened our understanding of the environmental and genetic exposures that cause this aggressive disease, reviews of traditional and novel approaches to staging it, and the complex multimodality therapies that have improved outcomes from no long-term survival to 15–24% 5-year-survival with treatment. Up-to-date reviews of radiation therapy are presented, including the latest results and commentary on induction radiation and hemithoracic radiation after pleurectomy/decortication (P/D). This issue offers perspectives on novel systemic therapies (such as immunotherapy), adjuncts (such as intraoperative heated chemotherapy), and insight into disease-related and treatment-related complications, with nuanced presentation of the management of MPM that has metastasized to the abdomen and traditional approaches to peritoneal mesothelioma that is a primary malignancy of the abdomen.