The nonsteroidal anti-inflammatory drugs (NSAIDs) cover a wide range of selectivity, from the nonselective cyclooxygenase (COX) inhibitors to the preferential COX-2, and the newest coxibs, selective COX-2, with 1000-fold selectivities for COX-2. Coxibs belong to the distinct classes of sulphonamides, methylsulphones, and phenylacetic acid derivatives. The affinity of an inhibitor for COX-1 and COX-2 determinates its relative selectivity. Minor changes in the amino acid structure between the 2 enzymes results in different forms of their active sites. However, the primitive hypothesis of a dualism between an isoform totally inducible (COX-2) and the other isoform constitutive (COX-1) was not completely true. Thus, also selective COX-2 inhibitors have been shown to interact with gastrointestinal, renal, and cardiovascular systems. New insights into pharmacological data and side effect profile of coxibs have been reported in this review. They may reduce gastrointestinal-related risks, but when administered with low-dose aspirin, they could create an ulcerogenic dual-COX inhibitor. Moreover, by inhibiting COX-2, they could delay ulcer healing. Similarly to traditional NSAIDs, coxibs compromise the glomerular filtration rate in patients at increased risk, and may cause peripheral oedema and hypertension. According to the traditional ''COX-2 hypothesis'', they should not impair efficacy of coagulation. However, in combination with an oral anticoagulant they increase the International Normalized Ratio (INR) and, in some cases, cause bleeding. The altered balance between prostacyclin and thromboxane, due to selective inhibition of COX-2 without reducing COX-1, could promote a prothrombotic state and explain the observed increased cardiovascular risk. Finally, the role of COX-2 expression in the ischemic preconditioning mechanism and the recent discovery of a pro-oxidant activity of sulphones has been analysed.