Malignant mesothelioma (MM) is an aggressive tumor whose incidence is expected to rise in future years. Patients with this neoplasm have a poor prognosis. Immunotherapy has been shown to be effective in some neoplasms (e.g. melanoma), significantly improving their prognosis but we do not yet have sufficient data on the capability of MM cells to elicit an immune response. A "three step" event is required to determine an immune response: adhesion, recognition, and costimulation between the antigen presenting cells and the immunoeffector cells. Lack of one of these three steps leads to a defective immune response. The most important mechanism determining the defective immune response to the tumor cells is supposed to be the deficiency of the molecules involved in this "three step event", the release of immuno-depressant factors by the tumor cells and/or the tumor infiltrating cells and the lack of surface immunogen epitopes. Investigations on MM cells are not univocal, suggesting that, at least in some cases, an effective immune response to this neoplasm can occur. Blocking the release of immunodepressant factors by malignant mesothelioma cells and identification of effective, specific immunogen epitopes seem to be the most promising objective to achieve.