The vascular endothelium is a dynamic cellular interface between the vessel wall and bloodstream where it regulates the physiological effects of humoral and biomechanical stimuli on vessel tone and remodeling. With respect to the latter hemodynamic stimulus, the endothelium is chronically exposed to mechanical forces in the form of cyclic circumferential strain, resulting from the pulsatile nature of blood flow, and shear stress. Both forces can profoundly modulate endothelial cell (EC) metabolism and function, and under normal physiological conditions impart an atheroprotective effect which disfavors pathological remodeling of the vessel wall. Moreover, disruption of normal hemodynamic loading can be either causative of or contributory to vascular diseases such as atherosclerosis. EC-matrix interactions are a critical determinant of how the vascular endothelium responds to these forces and unquestionably utilizes matrix metalloproteinases (MMPs), enzymes capable of degrading basement membrane and interstitial matrix molecules, to facilitate force-mediated changes in vascular cell fate. In view of the growing importance of blood flow patterns and mechanotransduction to vascular health and pathophysiology, and considering the potential value of MMPs as therapeutic targets, a timely review of our collective understanding of MMP mechanoregulation and its impact on the vascular endothelium is therefore warranted. More specifically, this review will primarily summarize our current knowledge of how cyclic strain regulates MMP expression and activation within the vascular endothelium and subsequently endeavour to address the direct and indirect consequences of this on vascular endothelial cell fate. Possible relevance of these phenomena to vascular endothelial dysfunction and pathological remodeling will also be addressed.