Malignant pleural mesothelioma is an aggressive malignancy with no known single curative modality. Most patients are candidates for chemotherapy at some point in their treatment, but no standard regimen has been established. Several phase II single-agent and combination chemotherapy studies have been performed over the past 2 decades. Although the true impact of chemotherapy in mesothelioma remains to be determined, agents with consistent antitumor activity include doxorubicin, platinum agents, and antimetabolites. Combination chemotherapy is associated with higher response rates, but not necessarily longer median survivals. Large randomized trials, which are currently ongoing or have been performed in the past few years, will yield important answers in regard to the role of chemotherapy and the efficacy of various single and combination chemotherapy agents. Furthermore, the biologic and genetic studies of mesothelioma have identified several receptor tyrosine kinases that are aberrantly expressed in these tumors. Orally available small molecule inhibitors of several receptor tyrosine kinases have been developed and are now being evaluated in clinical trials.