Selective cyclooxygenase-2 (COX-2) inhibitors are used for the treatment of inflammation and pain while having the reported advantage of fewer upper gastrointestinal adverse effects compared to traditional nonsteroidal anti-inflammatory drugs. Although fewer adverse effects occur, there is still a risk for developing upper gastrointestinal adverse effects. Clinical practitioners have increased concern regarding this risk. The belief that COX-2 inhibitors are safe for the gastrointestinal tract has been questioned. This has encouraged the proposal of several explanations on the mechanism of gastromucosal injury and healing relative to COX isoenzymes. These mechanisms are delineated in the following review, along with the gastrointestinal safety, risk factors, clinical and case studies, and cost effectiveness of the COX-2 inhibitors.