Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs worldwide. Nevertheless, their intake is frequently associated with gastrointestinal side effects, representing still an important medical and socio-economic problem. In recent years efforts focused on the development of highly selective COX-2 inhibitors with an improved gastric tolerability profile. However, severe cardiovascular adverse reactions challenged the initial enthusiasm in this new class of anti-inflammatory drugs. In addition, the market withdrawals of some coxibs led to a relative reluctance in prescribing COX-2 inhibitors in clinical practice. As a consequence, the interest for alternative approaches to reduce gastrointestinal side effects associated with NSAIDs has re-emerged. There are two main components of gastric damaging properties of NSAIDs: (1) the acute toxicity associated with the short-term intake of NSAIDs, which is principally caused by local irritation of the gastric mucosa (2) the chronic toxicity resulting mainly from systemic effects associated with prolonged administration of NSAIDs. Based on that background two different approaches were pursued in the search for GI sparing NSAIDs: a) modification of classical NSAIDs by associating them with phospholipids, cyclodextrins, or chemical moieties that release gastroprotective mediators and b) defining novel targets as well as developing new compounds like dual COX/5-LO or mPGES-1 inhibitors. This review provides the first comprehensive overview of all currently applied approaches taken to improve the risk-benefit ratio of NSAIDs focusing on the structure activity relationships and the respective mechanism of action underlying the individual approaches. The insight gained in this review is useful for further research activity in this field.