A paradigm shift has recently occurred in the clinical management of peritoneal surface malignancies (PSM). Once regarded as end-stage disseminated conditions only to be palliated, PSM are now increasingly recognized as local-regional disease entities amenable to potentially curative therapies. Better knowledge of the natural history and patterns of disease-progression has evolved into a novel treatment approach combining aggressive cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy, to treat the microscopic residual disease. Such a complex comprehensive treatment has reportedly resulted in a survival improvement over historical controls, and it is gaining an increasing acceptance as standard of care for selected patients with peritoneal metastases from gastrointestinal and gynecological tumor and rare primary peritoneal malignancies. This article addresses the rational bases supporting the comprehensive treatment of PSM. The biology and patho-physiology of peritoneal tumor dissemination, with their implication on surgical and local-regional management are reviewed. The cytoreductive surgical procedures and intraperitoneal chemotherapy administration techniques are described, together with the theoretical principles from which have originated. The main controversial issues in the operative management of PSM are discussed, focusing on the technical variants adopted in our institution. The most recent literature data on both patient selection and appropriate indications for combined treatment are presented. Additionally, a brief overview of treatment results and long-term outcomes following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the different PSM is provided.