This article reviews current knowledge on the biology of photodynamic therapy on normal and diseased tissues in the gastrointestinal tract. There is little effect on connective tissue, so the mechanical integrity of the luminal gut is well preserved, even with full thickness damage. This makes photodynamic therapy suitable for treating small tumors, but strictures may occur after circumferential treatment of conditions like Barrett’s esophagus unless a musclesparing photosensitizing agent is used. Animal studies show that the pancreas and surrounding tissues can tolerate photodynamic therapy, justifying pilot clinical trials on percutaneous, interstitial photodynamic therapy for localized, inoperable pancreatic cancers.