On the surface of endothelial cells (ECs) lies the glycocalyx, a barrier of polysaccharides (long sugars) that isolates the ECs from the blood. The role of the glycocalyx is dynamic and complex, thanks to not only its structure, but its vast number of components, one being hyaluronan (HA). HA is a critical component of the glycocalyx, having been found to have a wide variety of functions depending on its molecular weight, its modification, and receptor-ligand interactions. As HA and viscous blood are in constant contact, HA can transmit mechanosensory information (what is rubbing up or pulling against the outside of the EC) directly to the cytoskeleton of the ECs. The degradation and synthesis of HA directly alters the permeability of the EC barrier, changing what cells can pass through. HA modulation not only changes the physical barrier but also can signal the start of other pathways. EC proliferation and angiogenesis (production of new blood vessels) are in part regulated by HA fragmentation, HA-dependent receptor binding, and downstream signals. The interaction between the CD44 receptor and HA is a driving force behind leukocyte recruitment, but each class of leukocyte still interacts with HA in unique ways during inflammation. HA regulates a diverse repertoire of EC functions.