Malignant pleural mesothelioma continues to be a clinical challenge and its incidence will continue to increase worldwide. Once diagnosed with pleural mesothelioma, patients nearly invariably die of the disease. While the benefit of chemotherapy for advanced disease has been established, many other aspects of treatment continue to be controversial, in particular in regard to surgery and radiotherapy. However, the best survival data is reported from groups using multimodality treatment including surgery for patients qualifying from a tumor stage - and functional perspective. Therefore, efforts should focus on improving staging systems. Translational studies should be included with the final aim of finding reliable markers for response to therapy. Despite both, the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development, the number of new treatments that have been approved for patients has not increased. As mesothelioma is a rare disease, the number of patients is limiting and more innovative trial designs (such as multi-arm multi-stage trials ) using cooperative platforms to eliminate less effective treatments may be the best way forward.