AbstractHeparin and heparan sulfate (HS) are glycosaminoglycans (GAGs) that are synthesized in the tissues and organs of mammals. They are synthesized and attached to a core protein as proteoglycans through serine–glycine concensus motifs along the core protein. These GAGs are linear polysaccharides composed of repeating disaccharide saccharide units that are variously modified along their length. As a consequence of these modifications naturally occurring heparin and HS are extremely heterogeneous in their structures. A diverse range of proteins bind heparin and HS. The types of proteins that bind are dictated by the structure of the HS or heparin chains with which they are interacting. Heparan sulfates play major roles in tissue development and in maintaining homeostasis within healthy individuals. Recent genetic studies illustrate that alterations in their structural organization can have important consequences often giving rise to, or directly causing, a disease situation. A greater understanding of the repertoire of proteins with which heparin and HS interact and the diseases that can be caused by perturbations in the structures of heparin and HS proteoglycan may provide insights into possible therapeutic interventions. These issues are discussed with a focus on musculoskeletal phenotypes and diseases. WIREs Syst Biol Med 2011 3 739–751 DOI: 10.1002/wsbm.149This article is categorized under: Physiology > Mammalian Physiology in Health and Disease