The (dramatic, unexplained) decline in the incidence and mortality of gastric cancer in the United States occurred in 1930 and has continued to decline over the past 50 years. In the last 30 years, the 5-year survival rate for gastric adenocarcinoma in the United States has improved from 15% to 29%. Comparison of 5-year survival rates for gastrointestinal tumors over time Gastric cancer accounted for 5.7% of cancer-related deaths in 1967, and we expect it to account for only 1.9% of cancer-related deaths in 2014. Yet gastric cancer remains the second leading cause of cancer death worldwide. The risk of stomach cancer is higher in patient groups with low socioeconomic status. People who migrated from areas with high or low rates of gastric cancer maintained their susceptibility to gastric cancer, yet the risk of gastric cancer in their offspring was similar to the prevalent risk in the post-migration area. These observations suggest that environmental exposure (most likely at a young age) is associated with the development of gastric cancer, with dietary carcinogens and H. pylori being the major carcinogenic factors. In the last 50 years, gastric adenocarcinoma can be subdivided into 2 types: the intestinal type, characterized by ulcerative injury of the gastric sinus region, the lesser curvature (heavier than superficial sinusitis), often caused by H. pylori infection; and the diffuse type, involving the entire stomach, mostly without mucosal ulceration, causing loss of distensibility (leathery stomach), associated with reduced expression of calmodulin, and usually with a poor prognosis. Although the incidence of diffuse gastric cancer is similar in most people, intestinal gastric cancer is more common in areas with high incidence of gastric cancer and rare in areas with reduced incidence of gastric cancer. Germ-line mutations in calmodulin (CDH1), which encodes a cell adhesion protein, is an autosomal dominant disorder associated with an increased incidence of diffuse gastric cancer in young, asymptomatic carriers. Surgical treatment: Over the past 20 years, the radiographic-ultrasound double-contrast examination used to evaluate patients for upper abdominal discomfort has been replaced by CT scans and esophagogastroscopy. Although subtotal gastrectomy remains the surgical option for patients with distal, intestinal gastric cancer, patients with diffuse gastric cancer are now treated with preoperative chemotherapy or radiotherapy because of the poorer outcomes of surgery alone in these patients. In regions with a high incidence of gastric cancer (e.g., Asia), a large number of lymph nodes are routinely removed during surgery for gastric cancer. A number of randomized trials have been conducted to compare the efficacy of this surgical approach, called D2 or D3, with surgery that removes only a small number of lymph nodes. These trials have shown a more limited improvement in the efficacy of the more aggressive procedure, probably because the tumor control effect of D2/D3 surgery is offset by an increase in perioperative complication rates and mortality. Pharmacotherapy: We investigated the efficacy of multiple fluorouracil-based combination chemotherapy regimens (e.g., fluorouracil, folinic acid, and oxaliplatin, or FOLFOX regimen; epirubicin, cisplatin, and fluorouracil, or ECF regimen; and docetaxel, cisplatin, and fluorouracil, or TCF regimen) for the treatment of advanced gastric cancer. Although remission rates vary and median survival times are generally less than 12 months, the main differences between the regimens are the severity and cost of adverse effects. Adding trastuzumab to the chemotherapy regimen in the 15% of patients with human epidermal growth factor receptor 2/neu overexpressing cancers extended median survival by 2.7 months. Adding bevacizumab to the chemotherapy regimen did not prolong median survival. However, a recently developed monoclonal antibody to the vascular endothelial growth factor receptor (ramucirumab) appears to be of interest for investigation. Results of trials conducted in Asia and Europe have shown that adjuvant or perioperative chemotherapy can improve surgical cure rates. Probably because of the lesser use of extensive surgical treatment, postoperative radiotherapy has the best efficacy in the United States. The efficacy of the more intense ECF chemotherapy regimen was not improved compared to the fluorouracil + folinic acid regimen (as part of the adjuvant radiotherapy regimen). Major research advances in the field of gastric cancer during the five decades are summarized as follows: important observations and advances in the field of gastric cancer between 1964 and 2014 1. Incidence and mortality rates of gastric cancer in the United States continue to decline 2. Gastric adenocarcinoma can be subdivided into 2 types: intestinal (ulcerative lesions in the sinus of the stomach following atrophic gastritis) diffuse (submucosal infiltration with loss of distensibility) 3. Helicobacter pylori infection associated with intestinal subtypes 4. Germline mutations regulating E-cadherin calmodulin (CDH1) are associated with familial gastric cancer 5. limited improvement in the efficacy of D2/D3 surgery, probably because the effect on tumor control is offset by increased complication rates and mortality in the perioperative period 6. adjuvant radiotherapy treatment prolongs patient survival