Malignant Pleural Mesothelioma (MPM) continues to be a challenging problem; because few patients may be treated with radical surgery and conventional chemotherapy have achieved very dismal results. Pemetrexed is a new drug with multitarget antifolate activity which seems to be particularly active in many solid tumors and also in MPM. The principal clinical experiences of pemetrexed alone or in combination with other compounds, chiefly platinum and its derivative, are reported. The Italian study on 1114 cases of MPM treated over 30 months is discussed and the definitive results will be available after a complete external review of all responsive patients.