The surface of endothelial cells (ECs) is decorated with a wide variety of membrane-bound macromolecules that constitute the glycocalyx (GCX). As the most apical structure on the EC, the GCX senses the force (shear stress) of flowing blood and transmits it via the cytoskeleton throughout the cell to sites where transduction of force to biochemical response (mechanotransduction) may occur. In this presentation the structure of the GCX and many of the experiments that demonstrate its role in mechanotransduction and vascular remodeling will be reviewed. Experiments with enzymes that degrade specific glycosaminoglycan components have been used to show that the GCX mediates the shear-induced production of nitric oxide, a central process in cardiovascular control, while the same enzyme treatments do not affect shear-induced production of prostacyclin, another hallmark of EC mechanotransduction. These experiments reinforce the concept of distributed sites of mechanotransduction in EC. The characteristic remodeling of the EC cytoskeleton and intercellular junctions in response to shear stress are dependent on the GCX as well, and the experiments that support the role of the GCX in these processes will be reviewed as well.