Atherosclerosis, the leading cause of morbidity and mortality in developed nations, is a chronic inflammatory disease of arteries. In large and medium-sized vessels, the atherosclerotic burden is focal and non-random, despite the systemic nature of risk factors. This observation has prompted numerous studies over the past two decades that have evaluated the relationship between blood flow, endothelial function and plaque localization. The recent discovery of microRNAs (miRNAs) that are sensitive to distinct flow conditions has added a new layer of complexity to the pathophysiology of atherosclerosis, but may ultimately help us better understand the disease process. In this manuscript we will briefly review the most commonly used in vitro and in vivo model systems developed to study the relationship between flow, endothelial function and plaque development. We will also provide a brief summary of shear sensitive miRNAs that have been shown to modulate inflammatory signaling pathways and atherosclerotic burden through changes in the endothelial gene expression.