The promotion of the concept of cytoprotection has fostered hopes that the use of co-prescribed mucosal protective agents would revolutionize the prevention of NSAID-induced ulcers and supply the basis for novel ulcer therapy. Prostaglandins do not, however, accelerate ulcer healing when applied at doses that exert an unequivocal cytoprotective activity. Attempts have therefore been made in recent years to create new less-toxic NSAIDs, such as combined lipoxygenase/cyclo-oxygenase inhibitors, NSAIDs coupled to an NO donor and so-called COX-2 inhibitors. All these preparations do in fact exert a diminished gastrointestinal toxicity. There is however increasing evidence accumulating from studies performed in and outside our laboratories that in chromic ulcer models their increased gastrointestinal tolerance is not necessarily reflected by non-interference with ulcer healing. It is thus mandatory to distinguish between cytoprotective and healing properties of drugs interfering with the cyclo-oxygenase pathway.