Clotrimazole (CTZ; bispheny l (2-chlorophenyl)-methan)) is an N-substituted imidazole drug that is used therapeutically as a topical antifungal agent. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that both CTZ and its major metabolite 2-chlorophenybiphenylmethanol (2CLBPM) have LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surface CTZ is found to abound in electron-deficient regions so that it can react with cellular nucleophiles such as glutathione and nucleobases in DNA thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage. However, because of kinetic inertness of CTZ, the rates of such adverse reaction are expected to be low unless speeded up enzymatically.