Atherosclerosis is a chronic inflammatory disease that originates at regions of arteries exposed to disturbances in fluid flow and results in progressive plaque formation in those areas. Recent work on cellular responses to flow has identified potential mechanosensors and pathways that may influence disease progression. These results led us to hypothesize that the same mechanisms that mediate adaptive responses in the vasculature become maladaptive at sites of disturbed flow. Subsequent changes in gene expression and matrix remodeling help to entrain these inflammatory pathways. These events synergize with systemic risk factors such as hyperlipidemia, smoking, and diabetes, leading to disease progression.