It was hypothesized over 40 years ago that a decrease in the oxygenation of the vascular wall might somehow be involved in atherogenesis. Recent studies concerning the mechanism of oxygenation indicate that diffusion through plasma is of major importance, meaning that a moderate, prolonged hypoxia could be induced by small decreases in the oxygen diffusivity. Combining all of this leads to a comprehensive theory of atherosclerotic change, indicating how aging, smoking, diabetes, hypercholesterolemia and hypertension are correlated with the disease, and suggesting methods of prevention (or reversal).