Malignant pleural mesothelioma is a tumor very difficult to diagnose and with a very controversial therapy. We describe an illustrative case with development of pleural overflow and detection of high adenosine-deaminase levels. Surgical resection combined with radiotherapy and/or chemotherapy is the current therapeutics. We describe the state-of-the-art advances in the immunohistochemical diagnosis and therapeutics and we stress the need to conduct cooperative studies in order to achieve a better knowledge of the prognosis factors, an effective step-by-step approach and innovative therapy strategies.