Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the most widely used class of therapeutic agents. By inhibiting cyclooxygenase (COX) and reducing gastrointestinal prostaglandins, they provide effective analgesia and suppress inflammation in a variety of conditions. However, through the same mechanism of COX inhibition, they also cause significant gastrointestinal toxicity. One of the most common methods to reduce NSAID-induced gastrointestinal toxicity has been to co-prescribe prophylactic therapies such as acid-reducing agents or the synthetic prostaglandin analogue, misoprostol. More recently safer NSAIDs, such as the COX-2 specific NSAIDs or the nitric oxide-releasing NSAIDs, have been developed or are currently in development. This article reviews mechanisms of NSAID-induced gastrointestinal toxicity. Also reviewed are data on the gastrointestinal consequences of the prophylatic co-therapies, COX-2 specific NSAIDs and nitric oxide-releasing NSAIDs.