Forces that are associated with blood flow are major determinants of vascular morphogenesis and physiology. Blood flow is crucial for blood vessel development during embryogenesis and for regulation of vessel diameter in adult life. It is also a key factor in atherosclerosis, which, despite the systemic nature of major risk factors, occurs mainly in regions of arteries that experience disturbances in fluid flow. Recent data have highlighted the potential endothelial mechanotransducers that might mediate responses to blood flow, the effects of atheroprotective rather than atherogenic flow, the mechanisms that contribute to the progression of the disease and how systemic factors interact with flow patterns to cause atherosclerosis.