Nearly all patients with malignant pleural mesothelioma (MPM) progress during or after standard first-line treatment with pemetrexed plus a platinum compound. Second-line therapies are being increasingly used in clinical practice, but their role is still unproven, and the optimal regimens remain to be defined. Published studies have frequently severe limitations, due to the small number and to the heterogeneity of patients included. New treatment options are eagerly awaited. In selected cases with a prolonged disease control after first-line chemotherapy, re-treatment with pemetrexed seems to be the best option. In the other cases, patients should be enrolled whenever possible in clinical trials. Single-agent chemotherapy remains a reasonable option for palliation.