Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation but are frequently associated with gastrointestinal side effects, including life-threatening bleeding or perforation of gastroduodenal ulcers. Conventional NSAIDs are nonselective inhibitors of two isoforms of cyclooxygenase (COX): COX-1 and COX-2. The inhibition of COX-1 is believed to be responsible for inducing mucosal injury primarily by impairing prostaglandin-dependent mucosal protective mechanisms. The latest development in reducing the incidence of ulcers and ulcer complications associated with conventional NSAIDs is the use of recently approved COX-2-specific inhibitors (CSIs). This article critically reviews the data on gastrointestinal toxic side effects for conventional NSAIDs without as well as with prevention therapy. In addition, we compare these data with those for the CSIs, namely, celecoxib and rofecoxib. Finally, we offer recommendations on the clinical use of these drugs, emphasizing the need to balance clinical effectiveness with the avoidance of potential gastrointestinal side effects.