Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective treatments for pain and inflammation. They have a substantial toxicity profile with side effects mainly affecting the gastrointestinal tract, heart and kidneys. Although they comprise a chemically diverse group of drugs, NSAIDs are unified by a common mode of action - the ability to inhibit the enzyme cyclo-oxygenase (COX). This also accounts for much of their toxicity. The enzyme exists in at least 2 isoforms. COX-1 generates prostaglandins with physiological functions, COX-2 is induced by inflammation and its physiologic functions are unclear at present. Conventional NSAIDs, like diclofenac, ibuprofen, and naproxen, are non-selective COX inhibitors, blocking the production of both physiologic and inflammatory prostaglandins. In this chapter, we describe the main ‘predictable’ gastrointestinal, cardiac and renal toxicities that can be explained by such blockade and review the supporting clinical and epidemiological evidence In the gastrointestinal tract, the side effects associated with conventional NSAIDs are both local and systemic, and include ulceration, bleeding, perforation, and obstruction. The upper gastrointestinal tract is more commonly affected than the lower. The cardiac and renal side effects are most likely to occur in patients with existing heart or kidney disease, where prostaglandins play an essential role in maintaining the vasoconstrictor/dilator balance necessary for homeostasis. The patients at highest risk of toxicity are the elderly, those with a prior history of ulceration or bleeding, and those with a history of cardiac disease. Among such patients, the decision to prescribe NSAIDs requires careful consideration of the potential benefits and harms.