Malignant pleural mesothelioma (MPM) is an uncommon malignancy characterized by a rapid clinical course. Few patients are possible candidates for radical surgery. According to most reviews, radiotherapy has a limited role in the treatment of MPM. The role of chemotherapy in the management of pleural mesothelioma still remains uncertain. The available data indicate that although 10-20% of patients are known to achieve on objective response to a number of chemotherapeutic agents, the impact on survival appears limited and improvement in the quality of life remains uncertain. The results of combination chemotherapy are comparable to those of single-agent chemotherapy and no major difference is detectable among the various combinations. Prospective phase II trials are recommended for the identification of new active treatments while large-scale randomized phase III trials are needed to identify the best available treatment. In addition, new standard criteria for eligibility and response assessment are required. This paper reviews the available literature on the systemic drug therapy of MPM.