Malignant mesothelioma is an aggressive, but relatively rare, malignancy, affecting the pleura and peritoneum. The prognosis for malignant pleural mesothelioma (MPM) is poor, with median survival in the range of 8-14 months, depending on stage and presentation of disease. Long-term results of available treatments are disappointing not only in terms of prognosis, but also of local control of the disease. Therefore, relief of symptoms and improvement of quality of life parameters are the short-term goals of therapy. In advanced disease not amenable to any local approach, such as surgery, combination chemotherapy represents the current standard of care. At present, the regimen of cisplatin/pemetrexed is the medical treatment of choice. This review summarizes standard chemotherapy options and focuses on the molecular basis of the newest biologically targeted therapies to be implemented in the near future, in the management of MPM.