Gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma are related diseases with environmental and genetic determinants. The genetic changes are relevant in 2 distinct ways. First, there are heritable variations in germline DNA that may influence the individual susceptibility to cancer. Second, there is an accumulation of somatic-cell genetic and epigenetic changes within the epithelium during the metaplasia-dysplasia-carcinoma sequence, which may be an important determinant for the likelihood for cancer progression. Esophageal cancer occurring in the context of a familial syndrome is rare and most cases are sporadic. The sporadic cases still may have heritable germline influences, but these are likely to involve multiple, low-penetrance susceptibility genes. To date, the relative contribution and identity of such genes are unknown. However, in the future the identification of susceptibility genes could have important public health implications for patient management. With regard to the epithelium, a map gradually is being created of the frequently occurring alterations. Some of these changes are critical whereas others are bystanders. As well as the identification of abnormalities in target genes, it also is possible to determine the global gene expression profile of these diseases and to correlate this profile with clinical outcome. It is hoped that these complementary approaches will enable patients to be stratified in terms of their cancer risk so that prevention, surveillance, and treatment strategies can be targeted appropriately. At the current time, genetics does not influence routine clinical management of patients with gastroesophageal reflux disease, Barrett's esophagus, or esophageal adenocarcinoma.