Using Barrett's esophagus and Crohn's disease as models of gastrointestinal disorders, a number of key mechanisms of cell injury and death and chronic inflammation are reviewed. Among them are the roles of impaired osmoregulation, elevated cytosolic calcium, activation of the mitochondrial permeability transition and levels of cytosolic adenosine triphosphate as determinates of cell death as well as the role of inflammatory cells, cytokines, NOD2 gene products, and reactive oxygen species in chronic inflammation. Further, the basis for the link between inflammation and cancer risk in Barrett's esophagus and Crohn's disease is described.