Gastric cancer's (GC) incidence shows large geographic differences worldwide with the lowest rates occurring in most Western industrialized countries including the United States and the United Kingdom; in contrast, relatively high rates of GC occur in Japan, Korea, China, and South America, particularly Chile. The Laurén classification system classifies GC under two major histopathological variants: 1) an intestinal type and 2) a diffuse type. The intestinal type is more common in the general population, more likely to be sporadic and related to environmental factors such as diet, particularly salted fish and meat as well as smoked foods, cigarette smoking, and alcohol use. It exhibits components of glandular, solid, or intestinal architecture, as well as tubular structures. On the other hand, the diffuse type is more likely to have a primary genetic etiology, a subset of which, known as hereditary diffuse gastric cancer (HDGC), is due to the E-cadherin (CDH1) germline mutation. The diffuse type pathology is characterized by poorly cohesive clusters of cells which infiltrate the gastric wall, leading to its widespread thickening and rigidity of the gastric wall, known as linitis plastica. Helicobacter pylori infection is associated with risk for both the intestinal and diffuse varieties of gastric cancer. Germline truncating mutations of the CDH1 gene, which codes for the E-cadherin protein, were initially identified in three Maori families from New Zealand that were predisposed to diffuse GC. Since then, similar mutations have been described in more than 40 additional HDGC families of diverse ethnic backgrounds. It is noteworthy that two-thirds of HDGC families reported to date have proved negative for the CDH1 germline mutation. A number of candidate genes have been identified through analysis of the molecular biology of E-cadherin. Patients with evidence of the CDH1 germline mutation in the context of a family history of HDGC must be considered as candidates for prophylactic gastrectomy, given the extreme difficulty in its early diagnosis and its exceedingly poor prognosis when there is regional or distant spread. Specifically, the E-cadherin cytoplasmic tail interacts with catenins, assembling the cell-adhesion complex involved with E-cadherin mediated cell:cell adhesion. β-catenin and γ-catenin compete for the same binding site on the E-cadherin cytoplasmic tail, directly linking the adhesion complex to the cytoskeleton through α-catenin. β-catenin gene (CTNNB1) mutations have been described predominantly in intestinal-type gastric cancers and CTNNB1 gene amplification and overexpression have recently been described in a mixed-type gastric cancer. This paper reviews the genetics of both intestinal and diffuse types of gastric carcinoma, their differential diagnosis, molecular genetics, pathology, and, when known, their mode of genetic transmission within families. J. Surg. Oncol. 2005;90:114–133. © 2005 Wiley-Liss, Inc.