Hereditary Diffuse Gastric Cancer (HDGC) is a dominantly-inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in two genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. Here, we discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation and its natural history.