Atherosclerosis is the disease with the highest mortality in the western world. Despite its large socio-economical impact, the underlying mechanisms are only partially known. It has been accepted for decades that atherosclerosis is a lipid driven disease, despite the fact that risk factors related to lipid metabolism only partially explain atherogenesis. Furthermore, new therapies specially focussed upon lipid metabolism only partially reduce plaque size. Recently two concepts – inflammation and blood flow/shear stress – have undergone a renaissance and gained a lot of interest as complementary explanations for plaque formation and these concepts will be the topic of the present manuscript. The role of inflammation became apparent from a series of mouse studies where systematically parts of the immune system were knocked down, before the induction of atherosclerosis. These studies identified inflammation as an independent mechanism attributing to plaque formation, and based upon these results and further studies atherosclerosis is considered a lipid driven inflammatory disease. The effect of blood flow in atherosclerosis is based upon the observation that plaques are not evenly distributed over the arterial system. These predilection sites are at or near side branches, i.e. where blood flow is non-uniform, or at the lesser curvature of bends, i.e. where blood velocity is relatively low. The effect of blood flow on the vessel wall is through shear stress which alters the physiology of endothelial cells. Shear stress (τ N/m2 or Pascal (Pa)) arises from the friction between two virtual layers in a fluid, and is induced by the difference in movement of the two layers (dv/dr s-1; in case of a cylindrical tube) and the “roughness” (or viscosity Pa.s) between these layers (τ=dv/dr*η). Shear stress also arises at the interplay between blood and the endothelial layer, where it induces a shearing deformation of the endothelial cells. This shearing deformation affects the phenotype of the endothelial cells and thereby the inflammatory component and plaque progression/composition. This paper describes the interaction between shear stress and inflammation. We will first describe recent findings on the sensing mechanism of shear stress by the endothelium. Subsequently, pro-inflammatory pathways modulated by shear stress in endothelial cells, followed by the effect of shear stress on plaque progression and plaque composition. At the end we will discuss new findings related to longitudinal plaque heterogeneity.