In the United States and in Europe, curative resections are possible in only 50% to 60% of newly diagnosed gastric cancer patients chosen to undergo surgery. For patients with higher stage tumors (T3-N(any)M0, T34N(any)M0, stages II, IIIa or IIIb), even after resection of all gross disease with negative margins, the recurrence risk is high. In the absence of earlier diagnosis, there is a clear need to develop new innovative treatment strategies that will increase the potentially curative resection rate and decrease the risk of recurrence after operation. The major treatment strategy pursued during the last 20 to 30 years has been postoperative systemic therapy with or without associated regional radiation. In general, using the systemic treatment regimens available in the past, no major decrease in recurrence rate has been shown. The use of routine postoperative systemic chemotherapy remains unproven. Several new approaches are currently undergoing intense study, in addition to chemoradiation. One involves the use of preoperative (neoadjuvant) systemic chemotherapy. The goal of these treatment plans is to allow an early attack on systemic micrometastatic disease, and by downstaging the primary tumor to increase the percentage of patients able to undergo curative resection. Phase 11 studies performed to date indicate acceptable toxicity to multidrug regimens including cisplatin-fluorouracil, variants of the 5-fluorouracil, doxorubicin, high-dose methotrexate (FAMTX) regimen, or other cisplatin-containing combinations. No increase in operative morbidity or mortality has been found. Large-scale trials using neoadjuvant therapy are in the advanced planning stage. A second approach (used with or without neoadjuvant therapy) is treatment with intraperitoneal adjuvant chemotherapy given in the immediate postoperative period. This strategy is based on the failure pattern of resected gastric cancer with its high rate of peritoneal and hepatic metastasis. In addition to phase II trials, several small-scale phase III studies have been completed. Although those which involve patients with known residual disease have, in general, been negative, studies in patients who were treated in the truly adjuvant setting (having undergone potentially curative resections with no residual disease) are more promising. Finally, chemoimmunotherapy has been extensively studied in trials in Japan and Korea. Thus, from the point of view of clinical practice, routine administration of intravenous postoperative chemotherapy has not yet shown clear evidence of benefit and the standard of care remains surgery alone. The most promising current approaches are neoadjuvant chemotherapy using newer combination regimens with or without postoperative intraperitoneal therapy, chemoimmunotherapy after surgery, and postoperative chemoradiation. National or international trials testing the hypothesis that these types of approaches are superior to expectant observation have a high priority. A large American intergroup trial is underway testing the concept of postoperative adjuvant chemoradiation. Additional trials involving preoperative and postoperative therapy are in the advanced planning stage.