The pathogenesis of nonsteroidal antiinflammatory drug (NSAID) induced gastrointestinal (GI) injury is complex and includes contributions from direct topical injury and reduced mucosal resistance due to indirect or systemic inhibition of mucosal prostaglandin (PG) synthesis. Some NSAID that cause less inhibition of gastroduodenal PG synthesis appear to cause less GI injury. NSAID induced GI complications include adverse symptoms, endoscopically observable mucosal damage, and ulcer complications. Ulcers are common in patients taking NSAID and are often asymptomatic; however, they may bleed or perforate. Prevention of GI complications can be approached by concomitant administration of a protective drug or by developing a safer NSAID. However, limitations of concomitant therapy with existing protective drugs suggest that new NSAID should be developed that are less harmful to the GI tract.