Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death in the world. Over the past 2 decades, many exciting discoveries regarding the genomics of gastric cancer have been made. There are 2 distinct histologic types of gastric adenocarcinoma, and these types differ in their epidemiology, pathogenesis, genetic profile, and clinical outcome. The development of new approaches to functional genomics has significantly improved our ability to explore molecular alterations underlying gastric carcinogenesis and progression. The pathogenesis of intestinal-type gastric cancer follows a multistep progression that usually is initiated by H pylori infection. A wide range of genetic and epigenetic abnormalities including point mutation, loss of heterozygosity, microsatellite instability, and hypermethylation are described in intestinal-type gastric cancer and its precursor lesions. In contrast to the intestinal-type, diffuse-type gastric cancer is defined by a lack of precursor lesions; mutation or epigenetic silencing of the E-cadherin gene appears to be the key carcinogenic event. An improved understanding of the genomics of gastric cancer should lead to the rapid development of novel diagnostic techniques and molecular-based treatment strategies.