Malignant pleural mesothelioma (MPM) is a highly fatal cancer of the pleura that has been defeating standard and investigational therapies since its first description. The efficacies of chemotherapy, radiotherapy, and surgical therapy are limited, and we have been writing for decades that improved therapies are needed. MPM is born of inflammation, and approximately 80% of cases are associated with the smoldering tissue inflammatory responses against the carcinogenic fibers of asbestos. Emerging data on the use of programmed cell death protein 1 immune checkpoint inhibitors were initially exciting, but response is less than 20% and these agents are finding their place on the list of approaches with narrow efficacy. Molecular targeted therapies have revolutionized the treatment of other cancers, commonly result in striking antitumor responses, and directly embody precision medicine. For an example, we prescribe drugs for some lung adenocarcinomas that target the secondary mutations that develop as a resistance mechanism to their initial targeted therapy. The discovery of molecular therapeutics for any tumor begins with identification of a target through investigation of the genomic, epigenomic, and transcriptomic drivers of its carcinogenesis. Such an advance could revolutionize the treatment of mesothelioma. A comprehensive dissection of MPM’s molecular structure was recently published by 2 groups, the first from the Brigham and Women’s Hospital and then from The Cancer Genome Atlas. In the Invited Expert Opinion article that follows, a practical account of the molecular underpinnings of MPM is eloquently presented by the Brigham group and will inspire the discovery and translation of novel molecular targets by mesothelioma investigators and practitioners.