The gastrointestinal tract is characterized by a rapid proliferation of stem cells that differentiate to become terminal mature cells and ultimately die through a genetically programmed form of cell death, termed apoptosis, which is responsible for maintaining of tissue size. Apoptosis has also been shown to play an important role in the pathophysiology of several gastrointestinal diseases. The development of many infectious and immune-mediated diseases, such as gastritis, coeliac disease, inflammatory bowel diseases, may be triggered by the prevalence of pro-apoptotic signals, whereas prolonged cell survival, due to apoptosis inhibition, may give rise to neoplastic clones. Elucidation of the biochemical pathways and of specific proteins regulating apoptosis may provide a remarkable opportunity to manipulate the life and death decisions of the gastrointestinal cells and to develop new therapeutic strategies. This review will deal with the mechanisms potentially involved in apoptosis and with the clinical relevance of this phenomenon in gastrointestinal diseases.