Pericardial mesothelioma is a rare cancer for which treatment options are limited. Operative intervention in pericardial mesothelioma is primarily for effusion control, for cytoreduction before multimodal therapy, or to deliver and monitor innovative intrapericardial therapies. Misdiagnosis is common. Early detection of the disease is the only hope for survival. Echocardiography, pathologic examination of pericardial fluid and pericardial biopsy, Gallium-67 scintigraph, Ber-EP4 antibody, and immunohistochemical procedures can be used. Magnetic resonance imaging is emerging as the best modality for demonstrating the nature and extent of the constrictive process, and the infiltration to the cardiac wall and great vessels. Failure of surgical techniques is usually associated with mesothelioma with entrapped heart, a large solid tumor mass, and a long history of pericardial effusion. If the tumor is localized, resection is the only hope for this rare, but lethal, entity. No single treatment modality is efficient by itself. The exact role of intracavitary chemotherapy or irradiation remains to be defined. Preliminary clinical application of photodynamic therapy and attempts at inhibiting the effects of growth factors, such as vascular endothelial growth factor and platelet-derived growth factor, and vaccine treatments are being explored. Adenoviral molecular chemotherapy recently completed phase I testing. Clinical trials for pleural mesothelioma remain important as clinicians seek to improve the outcome for patients with pericardial mesothelioma. Early diagnosis and multidisciplinary patient care is essential for improved surgical outcome. In the future, combined therapeutic strategies involving radical surgery, radiotherapy, adjuvant chemotherapy, and immunomodulation may have a role in the treatment of pericardial mesotheliomas.