The consistent topography, transmural involvement, and variation in severity and rate of progression in individual atherosclerotic lesions collectively indicate the dominant, primary role of hemodynamics. Specific anatomic configurations, vessels with elevated pressure, high velocity, or disturbed flow and iatrogenic production of accelerated atherosclerosis and its complications in therapeutic venous bypass grafts and arteriovenous shunts point to this role. The morphology and complications are consistent with the loss of cohesion and tensile strength of mural constituents and irreconcilably different from those of cholesterol- or fat-overfed animals and from other metabolic lipid storage disorders. These observations preclude dietary and circulating humoral factors and negate currently prevailing etiologic hypotheses that do not account for topography, pathogenesis, or complications. Atherosclerosis is the response to hemodynamically induced repetitive tensile stresses due to the pulse pressure and lesser flow-generated vibrations resulting in bioengineering fatigue occasioned by cumulative molecular fragmentation of mural constituents. This phenomenon also accounts for free-radical formation and lipoperoxidation. Atherosclerosis thus constitutes the combined manifestations of tissue fatigue and compensatory repair. When fatigue predominates, mural failure leads to the development of the primary complications (mural tears, dissection, ectasia, tortuosity, aneurysms). Lipid accumulation and thromboembolism are secondary phenomena. Fatigue onset is enhanced by hypertension and acquired or inherited defects of individual mural constituents. Iatrogenic and experimental production of atherosclerosis, its pathogenesis, and complications by hemodynamic means provides the ultimate proof of the causal role of bioengineering fatigue.