|Despite its decline in incidence, gastric adenocarcinoma (GAC) remains a worldwide disease with a dismal prognosis. It is noteworthy that gastric adenocarcinoma is heterogeneous with respect to anatomic location, histologic subtypes, and etiologic factors. Anatomically, gastric adenocarcinoma can grossly be split into two major types, cardia and noncardia gastric adenocarcinoma. Histologically, gastric adenocarcinoma may be subdivided into intestinal and diffuse types. Moreover, profiles of genetic alterations differ in relation to its anatomic locations and histologic subtypes of gastric adenocarcinoma. In terms of etiologic factors, the major environmental risks for gastric adenocarcinoma are traditionally linked to diet, smoking, and occupational exposure. Recently, abundant epidemiologic data and animal studies have documented that Helicobacter pylori is the major determinant of environmental risk for noncardia gastric adenocarcinoma. Based on multifactorial and multistage carcinogenesis and natural history of GAC, three strategies are identified for prevention of GAC.The first is primary prevention which emphasizes on risk appraisal and avoidance of risk factor exposure. Except hereditary factor, lifestyles such as diet, smoking, H. pylori are modifiable factors. The second is secondary prevention: including screening for general population and surveillance for high-risk group. Early diagnosis and preemptive ablation of precancerous lesions are two important measures. The third is tertiary prevention, which is current clinical practice. After diagnosis of GAC, surgery or chemotherapy is adopted to reduce recurrence and disabled. From the viewpoint of prevention and cost-effectiveness, primary and secondary prevention is obviously superior to tertiary prevention. Revelation of the connection between Helicobacter pylori infection and GAC has prompted new investigations pertaining to its basic and clinical aspects. H. pylori-induced persistent and uncontrolled gastric inflammation nearly always precedes the development of cancer and is instrumental in initiating a multistep process leading to carcinogenesis. Our community-based screening and eradication of H. pylori in Taiwan suggests early H. pylori eradication once in lifetimes seems feasible in reduction of gastric cancer and more cost-effective than surveillance strategy in prevention of gastric cancer.