Malignant pleural mesothelioma (MPM) is a disease usually unaffected by current therapeutic strategies, but for the majority of patients, the use of systemic chemotherapeutic drugs remains the only therapeutic option available. During the past 15-20 years, many phase II and a few phase III clinical trials have studied a large variety of drugs such as anthracyclines, alkylating agents, platinum compounds, taxanes, vinka alkaloids, and antifolates as single agents and in combination, with the aim to increase responses and survival. The combination of pemetrexed and cisplatin tested in the largest phase III randomized trial of malignant pleural mesothelioma ever conducted has become the current standard of care. New targeted therapeutic approaches with a variety of anti-growth factor drugs are currently undergoing investigation worldwide.