Malignant mesothelioma (MM) is a cancer with a high mortality rate and limited therapeutic options, typically presenting as a tumor in the serous membranes, most frequently in the pleura and the peritoneum rather than in the pericardium. There is much evidence that the immune system contributes to the biogenesis, growth and metastasis of MM through the unbalanced production of oxidants and cytokines, mesothelial cell DNA damage and the active support of MM neoangiogenesis and immunosuppression. Because classical therapeutic approaches are generally ineffective, novel immunological tools are being developed to target the immune cells infiltrating the MM foci and exploit the immune system to elicit an effective anti-tumor response. These therapies work by stimulating local inflammatory cells or transferring exogenously activated immunocompetent cells and by depleting MM-associated immunosuppressive clones to target the spontaneous specific immune responses against MM and to subvert MM driven immunoediting. This review summarizes the recent evidence on the immune system mechanisms that support MM development and the novel therapeutic approaches for strengthening the immune system by MM immunotherapy that are currently being developed in both experimental models and clinical trials. (C) 2012 Elsevier Ireland Ltd. All rights reserved.