Over the last decade, several improvements have been made in the diagnosis and treatment of malignant pleural mesothelioma, including better understanding of tumor biology, availability of more potent chemotherapeutic drugs, improved surgical management, and optimized multidisciplinary therapy. Radical tumor resection by means of extrapleural pneumonectomy (EPP) is now feasible with acceptable morbidity and mortality, even after neoadjuvant chemotherapy, if performed in specialized centers. To date, the best survival data have been reported after multimodality treatment strategies that include surgical resection. In this article, we discuss several strategies that involve EPP or pleurectomy/decortication in combination with various adjuvant and neoadjuvant therapies.