Malignant pleural mesothelioma is usually diagnosed as advanced disease, and treatment is not considered curative. Chemotherapy may palliate symptoms and improve both quality of life and survival for patients with advanced cancer, including those with mesothelioma. For the past decade, the combination of cisplatin with pemetrexed has been the standard of care for first line treatment of mesothelioma. This practice is predicated upon the results of the EMPHACIS trial, a phase III study comparing pemetrexed with cisplatin to cisplatin alone in patients with untreated mesothelioma. Most subsequent studies in cytotoxic chemotherapy have been small, non-randomized phase II studies and have not translated to new developments in the systemic treatment of this disease. Most recent trials use novel targeted therapies rather than cytotoxic chemotherapy, resulting in a paucity of recent data on cytotoxic chemotherapy and no clear advances over this decade, although recent data suggests that the addition of bevacizumab to cisplatin and pemetrexed provides a survival benefit. Herein, we review the current state of the art on chemotherapy in malignant mesothelioma.