Current evidence indicates that the ability of physical activity to sustain a normal phenotype of arterial endothelial cells (ECs) plays a central role in the beneficial effects of exercise (Ex) on atherosclerotic disease. Here we evaluate the strength of evidence that shear stress (SS) and/or circumferential wall stress (stretch) are the primary signals, produced by bouts of Ex, that signal altered gene expression in arterial ECs, thereby resulting in a less atherogenic EC phenotype. Current literature indicates that SS is a signal for expression of antiatherogenic genes in cultured ECs, in ECs of isolated arteries, and in ECs of arteries in intact animals. Furthermore, SS levels in the arteries of humans during Ex are in the range that produces beneficial changes. In contrast, complex flow profiles within recirculation zones and/or oscillatory flow patterns can cause proatherogenic gene expression in ECs. In vivo evidence indicates that Ex decreases oscillatory flow/SS in some portions of the arterial tree but may increase oscillatory flow in other areas of the arterial tree. Circumferential wall stress can increase expression of some beneficial EC genes as well, but circumferential wall stress also increases production of reactive oxygen species and increases the expression of adhesion factors and other proatherogenic genes. Interactions of arterial pressure and fluid SS play an important role in arterial vascular health and likely contribute to how Ex bouts signal changes in EC gene expression. It is also clear that other local and circulating factors interact with these hemodynamic signals during Ex to produce the healthy arterial EC phenotype. We conclude that available evidence suggests that exercise signals formation of beneficial endothelial cell phenotype at least in part through changes in SS and wall stretch in the arteries.