Red blood cells (RBCs) contain large amounts of iron and operate in highly 
oxygenated tissues. As a result, these cells encounter a continuous oxidative 
stress. Protective mechanisms against oxidation include prevention of formation 
of reactive oxygen species (ROS), scavenging of various forms of ROS, and repair 
of oxidized cellular contents. In general, a partial defect in any of these 
systems can harm RBCs and promote senescence, but is without chronic hemolytic 
complaints. In this review we summarize the often rare inborn defects that 
interfere with the various protective mechanisms present in RBCs. NADPH is the 
main source of reduction equivalents in RBCs, used by most of the protective 
systems. When NADPH becomes limiting, red cells are prone to being damaged. In 
many of the severe RBC enzyme deficiencies, a lack of protective enzyme activity 
is frustrating erythropoiesis or is not restricted to RBCs. Common hereditary 
RBC disorders, such as thalassemia, sickle-cell trait, and unstable hemoglobins, 
give rise to increased oxidative stress caused by free heme and iron generated 
from hemoglobin. The beneficial effect of thalassemia minor, sickle-cell trait, 
and glucose-6-phosphate dehydrogenase deficiency on survival of malaria 
infection may well be due to the shared feature of enhanced oxidative stress. 
This may inhibit parasite growth, enhance uptake of infected RBCs by spleen 
macrophages, and/or cause less cytoadherence of the infected cells to capillary 
endothelium.