At the time that the term glycocalyx ("sweet husk") was introduced as a description of the extracellular polysaccharide coating on cells (Bennett HS: 1963. Morphological aspects of extracellular polysaccharides. J Hist Cytochem 11:14-23.), early electron microscopic observations had shown that anionic polysaccharides were also presented by the inner surface of blood vessels but the length of these structures was considered to be small and their functional significance was unknown. Research in the past decades in the glycocalyx field has evolved, and recent estimations indicate that the endothelial glycocalyx constitutes a voluminous intravascular compartment that plays an important role in vascular wall homeostasis. Pathologic loss of glycocalyx may be associated with an impaired vascular wall protection throughout the circulatory system, whereas agonist-induced modulation of glycocalyx accessibility for circulating blood may constitute a physiologically relevant mechanism to regulate functionally perfused volume and exchange area at the microvascular level. Both aspects are discussed in the current review.