Treatment of malignant pleural mesothelioma continues to be frustrating regardless of the modality employed. Numerous trials of chemotherapeutic agents have been performed, but until recently, these studies were small and subject to inaccuracies of disease measurement. To our knowledge, no chemotherapeutic regimen has emerged as a standard of care. A review of the literature reveals that small activity against this disease has been shown by the anthracyclines, platinum compounds, and alkylating agents, whereas higher activity has been reported with the antimetabolites. The plant alkaloids have not demonstrated any activity against mesothelioma. Dose-escalated chemotherapeutic regimens may offer an advantage, whereas combination chemotherapy has not shown any benefit over single-agent therapy. Favorable responses have been reported with the administration of intrapleural biological response modifiers. Further trials and the investigation of new agents in the treatment of this disease are necessary.