Mesothelioma is a highly lethal tumor derived from mesothelial cells, and its global incidence is increasing because of widespread exposure of numerous individuals to asbestos in the last 50 years. Mesothelioma is largely untreatable with any of the therapeutic modalities. Recently, a novel multitargeted antifolate pemetrexed has shown promising activity against malignant pleural mesothelioma, producing response rates of up to 40% when used in combination with cisplatin. In a large phase III study, use of a combination of pemetrexed and cisplatin was associated with significantly improved survival time and with greater antitumor activity compared with cisplatin alone. This combination also gave a significant response rate of approximately 50% in patients with epithelioid malignant pleural mesothelioma. These clinical benefits of pemetrexed–cisplatin doublet have changed the perception of mesothelioma chemotherapy. Other combinations, including gemcitabine in combination with cisplatin, have also shown encouraging response rates. Prognosis depends on gender, clinical stage of the tumor, histological subtype, platelet count, leukocyte counts, and performance status. Radiotherapy can palliate mesothelioma patients with chest pain, and has been indicated to be of benefit for the prevention of malignant seeding along the tract of a chest tube or needle biopsy. Trimodality treatment using extrapleural pneumonectomy, radiation and chemotherapy has shown promising therapeutic value. The development of chemotherapeutic regimens and the favorable outcomes of trimodality have led to new combined modality trials. In Japan, multicenter national trials against mesothelioma will begin in the near future.