Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain and symptoms of arthritis and soft tissue inflammation. The gastrointestinal (GI) adverse effects such as gastric and duodenal ulcers and their complications are the major limitations to the prescription of these drugs. As many as 25% of chronic NSAID users develop peptic ulcer disease among which 2%-4% bleed or perforate. Hence, the emphasis has always been on developing novel NSAIDs without GI toxicity. Selective cyclooxygenase (COX)-2 inhibitors (coxibs) elicit less clinically significant GI damage and bleeding than conventional NSAIDs, but there are concerns about the cardiovascular safety of these drugs. New treatment modalities such as Nitric Oxide (NO) releasing NSAIDs, dual COX/5-lipooxygenase (5-LOX) inhibitors and selective inhibition of terminal Prostaglandin synthases may be superior to coxibs in terms of reducing toxicity and increasing potency and efficacy. The advent of new mediators (lipoxins, Hydrogen Sulfide) may offer new key targets for safer NSAIDs. Several Phosphatidylcholine (PC)-NSAIDs, which were found to have increased analgesic and antiinflammatory activity with significantly less gastric and intestinal damage in animal models, are now in the advanced clinical trial. The R-enantiomers of NSAIDs, which may be helpful in chemoprevention of cancer and Alzheimers disease, generally exhibit greatly reduced GI toxicity. The evolution of these different novel NSAIDs may provide new modalities of anti-inflammatory therapies with greatly reduced GI toxicity.