Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide, but they can cause serious gastrointestinal (GI) side effects. NSAIDs are capable of damaging the whole gastrointestinal tract. Cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been developed with the aim of maintaining the anti-inflammatory benefits but reducing gastrotoxicity. There is a good evidence that these drugs effectively prevent gastroduodenal ulcers and ulcer complications. Little is known about the side effects of these agents in the small and large intestine. There is an increasing evidence that COX-2 is constitutively expressed in the gastrointestinal tract and is important for the maintenance of bowel integrity. There have also been growing concerns about the potential for coxibs to increase the frequency of adverse cardiovascular events. The purpose of this review is to summarize recent knowledge about the safety profile of selective COX-2 inhibitors.