Maintaining intracellular redox balance through tightly controlled systems that regulate production (pro-oxidants) and scavenging (antioxidants) of reactive oxygen species (ROS) is critical for normal cell function. In the heart, ROS are produced primarily by mitochondria as a byproduct of electron transport and also by extramitochondrial enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Multiple antioxidants including superoxide dismutase, catalase, glutathione peroxidase, and thioredoxin/thioredoxin-reductase systems counterbalance ROS generation, preserving redox equilibrium. Disruption in this equilibrium leads to redox stress, of which 2 main types have been defined: oxidative stress and reductive stress. Oxidative stress, characterized by a shift in the oxidative:reductive potential to a more oxidative state because of increased ROS production by pro-oxidant enzymes and reduced antioxidant defense mechanisms to scavenge excessive ROS, plays a physiological role in aging and wound healing, and a pathophysiological role in atherosclerosis, hypertension, heart failure, and ischemia–reperfusion injury.1 Reductive stress, however, is characterized by an aberrant increase in reducing equivalents, such as reduced glutathione and reduced NADPH, increased activation of antioxidant enzymes and reduced pro-oxidant capacity, leading to a shift in the redox balance from an oxidative to a reduced state (Figure).2 Intuitively, one would consider activation of antioxidant systems as being redox-protective; however, growing evidence indicates that reductive stress may be even more injurious than oxidative stress through processes, whereby intrinsic cytoprotective defences negatively target the exact systems they should protect.3 In the heart, reductive stress has been linked to mitochondrial dysfunction, heart failure, myocardial ischemia–reperfusion injury, cardiac hypertrophy, and cardiomyopathy. These are the exact pathological conditions associated with oxidative stress. Then, how can both an increase in pro-oxidants and an increase in antioxidants or reductants lead to the same outcome?