The erythrocyte represents a major component of the antioxidant capacity of the blood through the enzymes contained in the cell, the glutathione system, and the low-molecular-weight antioxidants of the erythrocyte membrane. A further major red blood cell contribution is in regenerating consumed redox equivalents via the oxidative pentose phosphate pathway and glutathione reductase. Moreover, its extracellular antioxidant capacity, its mobility, and the existence of reducing equivalents far in excess of its normal requirements make erythrocytes function as an effective oxidative sink in the organism. That is why red blood cell metabolism and homeostasis strongly affect the antioxidant properties of the whole body. Conversely, the relation between macrocytosis and oxidative stress has not been fully delineated. Reviewing the mechanisms involved in red blood cell homeostasis in cases of redox imbalance is crucial in identification of factors that could potentially improve erythrocyte survival and defense against oxidant damage.