CD95 is a member of the tumor necrosis factor receptor family. It is constitutively expressed on the basolateral membrane of intestinal epithelial cells (IEC) and induces apoptosis when cross-linked by its natural ligand, CD95L. The significance of providing such a death-inducing mechanism in IEC is not yet clear. In recent years a multitude of studies have been published addressing the question of where and under which conditions CD95L is produced in the gut in the normal and neoplastic situation. Although some of these studies have considerably influenced our view on the role of the CD95/CD95L system, it appears necessary to critically review published data which are in part confusing and contradictory. To date compelling evidence of CD95L expression in untransformed IEC is lacking, and involvement of the CD95/CD95L system in the physiological epithelial cell turnover appears unlikely. Whereas CD95L is overexpressed in T-cells under inflammatory conditions, its significance for mucosal damage in inflammatory bowel diseases is obscured by possible redundancies in cell death mechanisms. Finally, recent data indicate that the intriguing CD95L counterattack concept in gastrointestinal tract cancer needs to be revised.