Malignant mesothelioma (MM) is an uncommon neoplasm that arises from the cells lining the body cavities, in particular the pleural and peritoneal cavities. The treatment of MM is a major challenge with frustrating results for clinicians and patients alike. Despite the adoption of newly developed radiotherapic and chemotherapic regimens, the prognosis remains dismal and only modest improvements have been obtained thus far. In this scenario, a better comprehension of the molecular patterns is of paramount importance. Cyclooxygenases catalyze the rate limiting step in the production of prostanoids. Accumulating data demonstrate that overexpression of these enzymes, and in particular of cyclooxygenases- 2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that inhibition of cyclooxygenases- 2 can delay or prevent certain forms of cancer. Aim of this review is to discuss the current state of the art in mesothelioma, with a particular emphasis on the recent advances in molecular pathogenesis uncovering several aspects of initiation and development of MM; in particular the role of COX-2 will be highlighted. Finally, potential novel therapeutic molecular targets will be discussed.