Naproxen (NAP) is a non-steroidal anti-inflammatory drug that has been widely used in the treatment of rheumatoid arthritis and osteoarthritis. Although NAP is considered to be safe, it has a number of side-effects including gastrointestinal toxicity, nephrotoxicity, jaundice and hepatotoxicity. The hypersensitive response of NAP is believed to be associated with hepatitic injury caused by the drug. It has been suggested that the electrophilic metabolites of NAP can cause depletion of cellular glutathione and thus compromising the antioxidant status of the cell and can also cause oxidation of nucleobases in DNA. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT (at B3LYP/6-31G* level) calculations show that NAP and all its metabolites are expected to be neither extremely inert kinetically nor highly labile. The presence of both electron-rich and electron-deficient regions on the surfaces of NAP and its metabolites indicates that they may be subject to both electrophilic and nucleophilic attacks. The latter means that they can react with cellular glutathione, causing its depletion and thus inducing cellular toxicity. However, the kinetic inertness of NAP and its metabolites means that the rates of such adverse reactions would be low.