Clofarabine (CLF) is a new purine nucleoside antimetabolite developed for the treatment of solid and hematologic tumours. In this study molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to gain information on the relative toxicity of CLF and its metabolites. The study shows that CLF and its metabolites have large LUMO-HOMO energy differences of the order 5.3 eV from DFT calculations, indicating that CLF and all its metabolites would be kinetically inert. The molecular surfaces of CLF and all its metabolites are found to possess significant amounts of electron-rich (yellow and red) and neutral (green) regions so that the compounds may be subject to electrophilic and lyophilic attacks. However, the molecular surfaces do not appear to abound in electron-deficient (blue) regions (although the presence may be significant in the case of CLF, 2CAD and CLFDP) so that the compounds generally may not react to any significant extent with cellular nucleophiles such as the reduced form of glutathione and nucleobases in DNA. This means that other factors besides glutathione depletion and DNA damage may be playing key role in toxicity of CLF and its metabolites.