Inhibitors of cyclooxygenases (COXs) are the most widely used drugs. They reduce discomfort and fever, inhibit peri-operative and inflammatory pain. These effects are largely mediated by inhibition of cyclooxygenase-1 and -2 (COX-1 and COX-2)-enzymes found throughout the body producing prostaglandins, which are important mediators of pain and fever, but also adaptive and protective reactions in many organs. A first step to reduce the overall toxicity and to increase the anti-inflammatory activity of these drugs was achieved with the development of acidic 'non-selective' (traditional) non-steroidal anti-inflammatory drugs (tNSAIDs). These agents distribute unequally throughout the body, reaching effective concentrations in inflamed tissue (effect compartment) for prolonged time periods. They can also reach effective concentrations in the bloodstream, kidney and gastrointestinal (GI) mucosa, where they can cause unwanted effects, such as GI toxicity, kidney dysfunction and cardiovascular impairment. All these effects are particularly prominent with compounds which are eliminated slowly [half-life (T((1/2))) >12 h] and thus also block prostaglandin production permanently outside the effect compartment. A second step towards improving safety was achieved with selective COX-2 inhibitors. These agents reduce the incidence of GI toxicity, pseudo-asthmatic reactions and blood loss following surgical interventions. However, they may be more toxic to the cardiovascular and renal systems than some tNSAIDs, possibly because they distribute homogeneously throughout the body and inhibit COX-2 in the endothelial layer of the vessels and the kidney permanently due to their slow elimination. Another step towards improvement in safety appears possible by combining both enzyme specificity and tissue selectivity, to achieve a further reduction of unwanted drug effects while maintaining the anti-inflammatory/analgesic efficacy.