Abstract: The red cell is a relatively abundant locus of both free radical generation and reaction. Erythrocytes have a high content of unsaturated membrane lipids, a rich oxygen supply and are densely packed with redox‐active hemoglobin residues. In response, red cells have a highly evolved and well‐integrated network of oxidant defense mechanisms that lend an ability to withstand oxidative stress. In the case of congenital hemoglobin mutations that underlie sickle cell disease, they become very susceptible to free radical‐mediated injury by virtue of enhanced endogenous rates of production of reactive species and impairment of tissue free radical defense mechanisms. In sickle cell disease, a combination of these susceptibility factors are hypothesized to lead to an overall impairment of vascular function, in large part due to loss of “bioactive” nitric oxide via the free radical‐mediated consumption of this vasoactive molecule.