In this review, we have discussed our current understanding of the barrier properties that are in place to protect the upper gastrointestinal mucosa from luminal acid, and the pathogenic mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce injury to the gastrointestinal tract. The changes in our view of the importance of NSAID-induced cyclo-oxygenase (COX) inhibition on the pathogenesis and prevention of NSAID-induced gastrointestinal injury is presented. The focus of this paper has been placed on the effects of NSAIDs on the mucosal surface, and specifically the effect of these powerful drugs in inducing changes in the hydrophobicity, fluidity, biomechanical and permeability properties of extracellular and membrane phospholipids. Lastly, recent evidence is presented that salicylic acid and related NSAIDs may alter the stability of membranes, inducing the formation of unstable pores that may lead to back-diffusion of luminal acid and membrane rupture. This understanding of the interaction of NSAIDs with membrane phospholipids may prove valuable in the design of novel NSAID formulations with reduced gastrointestinal side-effects.