The functional phenotypic plasticity of the vascular endothelium relies on the ability of individual endothelial cells to integrate and transduce both humoral and biomechanical stimuli from their surrounding environments. Increasing evidence strongly suggests that biomechanical stimulation is a critical determinant of endothelial gene expression and the functional phenotypes displayed by these cells in several pathophysiological conditions. Herein we discuss the types of biomechanical forces that endothelial cells are constantly exposed to within the vasculature, explain how these biomechanical stimuli serve as regulators of endothelial functionanddiscuss the increasing evidence that “atherosclerosis-protective” or “atherosclerosis-prone” haemodynamic environments can beimportant causative factors for atherogenesis via the differential regulation of endothelial transcriptional programmes.