Oxidative stress, as defined by Sies more than thirty years ago, has received much attention and has served as an important intellectual tool to understand the pathophysiology of many diseases and also of normal processes like ageing. However, recently the idea that the cells might suffer from reductive rather than oxidative stress and that such stress may be relevant in pathophysiology has gained momentum. Some time ago we defined reductive stress as a “as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state”. We postulated that reductive stress might be due, at least in part to a “small but persistent generation of oxidants that results in a hormetic overexpression of antioxidant enzymes that leads to a reduction in cell compartments”. Experiments showing reductive stress in experimental myocardial ischaemia in swine, in clinical studies in Alzheimer's disease patients and in normal individuals at high risk of developing Alzheimer's (because they carry the ApoE4 allele), will be discussed to highlight the role of reductive stress in these pathophysiological processes.