Iron(II) species can participate in the Fenton and Fenton‐like reactions to generate the hydroxyl radical that can oxidatively damage biomolecules and induce oxidative stress in biological systems. Many diseases, including neurodegeneration, cardiovascular disease and cancer, are associated with oxidative stress. However, it is proposed recently that hydroxyl radical would not be generated from the Fenton reaction under physiological conditions and thus would not cause oxidative stress in biological systems. This proposal may cause confusion for understanding oxidative stress and can also have impact on therapeutic strategies for the diseases associated with oxidative stress. In this Mini-review, the up-to-date convincing evidences of hydroxyl radical generation from the physiologically relevant Fenton‐like reactions of the iron(II) complexes with physiological ligands in human blood plasma, including histidine, citrate and phosphate, are succinctly reviewed. The oxidative damages caused by hydroxyl radical to biomolecules and cells are briefly summarized. These findings strongly challenge the above proposal.