Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and ultimately fatal cancer that was first recognized and described a century ago. It is a diffuse primary malignant condition arising from the mesothelial lining of the peritoneum, and its natural history is hallmarked by a propensity to progress almost exclusively within the abdominal cavity throughout the entire course of disease. Patients afflicted with DMPM most commonly present with nonspecific abdominal symptoms that lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for patients with DMPM without treatment is very short, averaging 6 months. Systemic chemotherapy using pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year. Many institutional reports have shown that in selected patients, operative cytoreduction and hyperthermic intraoperative peritoneal chemotherapy using cisplatin or mitomycin C is associated with long-term survival. Recent studies on the molecular biology of DMPM have yielded new insights relating to the potentially important role of the phosphatidylinositol 3-kinase/mammalian target of rapamycin and epidermal growth factor receptor pathways in this disease, which may translate into new therapeutic options for patients with DMPM.