The first description of glycosaminoglycans (GAGs) was by J. Mçller in 1836, who isolated ªchondrinº, a sugar-related substance from cartilage that was later shown to contain a sulfo group by Maerner (1889) and renamed ªchondroitsåureº [1]. It was not until 1935 that Karl Meyer discovered hyaluronic acid, initiating the exploration of GAG biochemistry and the identification of different types of GAGs. The past half-century has resulted in substantial progress in the elucidation of GAG fine structure, biosynthesis, and biological functions.GAGs are unbranched, polydisperse, acidic polysaccharides, often covalently linked to a protein core to form proteoglycans (PGs). GAGs extend from a protein core in a brush-like structure. The core protein size ranges from 10 kDa to >500 kDa, and the number of attached GAG chains varies from 1 to >100 [2]. Except for hyaluronic acid, all GAGs are biosynthesized as PGs. The linkage region is the same in all PGs (except for keratan sulfate) and consists of the tetrasaccharide ± glucuronic acid (GlcAp), galactose (Galp), Galp, and xylose (Xylp) ± linked to the hydroxyl group of serine in the polypeptide core (Fig. 15.1) [3]. PGs occur in the membranes of all animal tissues, intracellularly in certain cells (usually in secretory granules) or extracellularly in the matrix, where they are exported to perform a variety of biological functions.GAG biosynthesis is initiated with the synthesis of the core protein, rich in serineglycine repeats [4], to which the linkage region and GAG are attached. GAGs are characterized (with the exception of keratan sulfate) by a repeating core disaccharide structure comprised of uronic acid and hexosamine residues. The amino group of the hexosamine residue is either N-acetylated or N-sulfonated, the uronic acid being either D-glucuronic acid or L-iduronic acid. Moreover, the repeating disaccharide units are O-sulfonated to varying degrees at the 3-, 4-, or 6-positions of the hexosamine residue and at the 2-position of the uronic acid residues. The most common GAGs are heparin, heparan sulfate (HS), hyaluronic acid (HA), chondroitin sulfate (CS), dermatan sulfate (DS), and keratan sulfate (KS) (Tab. 15.1).