Chlorine dioxide (ClO2) is a highly effective disinfectant for food and potable water treatment. Till now, the action mode of ClO2 is still unclear. ClO2, can denature proteins by oxidizing tyrosine, tryptophan, and cysteine. We reviewed the pathways by which ClO02 reacts with important bio-molecules, as well as the primary target sites at individual cellular level of ClO2-induced biocidal effects.