Current evidence indicates that physical activity's abiltiy to sustain phenotype of arterial endothelial cells (ECs) plays a central role in the beneficial effects of exercise (EX) on atherosclerotic disease. 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 resulting in a less atherogenic EC phenotype. SS is a signal for expression of anti-atherogenic genes in cultured ECs, in ECs of isolated arteries and of arteries in intact animals. Further, SS levels in the arteries of humans during EX are in the range that produces beneficial changes. In contrast, oscillatory flow patterns can cause pro-atherogenic gene expression in ECs. In vivo evidence indicates that EX decreases oscillatory flow/shear in some portions of the arterial tree but may increase oscillatory flow in other areas of the arterial tree. Circumferential wall stress can also increase expression of some beneficial EC genes but circumferential wall stress also increases production of reactive oxygen species, and increases the expression of adhesion factors and other pro-atherogenic 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. We conclude that available evidence suggests that exercise signals formation of beneficial endothelial cell phenotype at least in part through changes in shear stress and wall stretch in the arteries.