A new concept in the natural history of gastrointestinal (GI) cancer suggests that recurrence of this malignancy can be separated into two types. Hematogenous and lymphatic metastases occur before surgical removal of the primary cancer. The spread of cancer to the resection site and to peritoneal surfaces occurs at the time of surgical removal of the primary tumor. Surgical trauma leads to a dispersal of malignant tumor emboli, which then implant within the raw tissue surfaces of the resection site and abraded peritoneal surfaces. Instillation of chemotherapy directly into the peritoneal cavity, as part of GI surgery, provides cytotoxic levels of drug that may change the natural history of GI cancer. The most common sites of disease recurrence have been, in the past, at the resection site and on peritoneal surfaces. With the optimal use of intraperitoneal chemotherapy, these sites of surgical treatment failure should no longer occur. Early phase I and II and pharmacologic studies suggest that an effective dose and schedule have been achieved, that toxicity is at reasonable levels, and that responses with small volumes of intra-abdominal cancer are exceptionally high. Chemotherapy that has an impact on the surgical event by decreasing cancer spread to the resection site and to peritoneal surfaces may significantly improve survival and quality of life in patients with GI cancer.