Heparan sulfate (HS) is a complex and highly active biopolymer that is synthesized as an alternating copolymer of hexuronic acid and glucosamine and modified at various positions with sulfate, which affects and controls its biological activities. 1, 2 Heparin, which we consider as an oversulfated intracellular variant of the ubiquitous HS, was first discovered in 1916 as an inhibitor of coagulation and was further developed for the next 20 years when it was first tested in patients as an anticoagulant drug in the mid 1930s. 3 Indeed, heparin is second only to insulin as what could be thought of as a very successful natural therapeutic agent. It received its name,“hepa” rin/“hepa” ran, because hepatic tissue was a common and abundant source from which it was first isolated and studied. HS was originally discovered as an impurity of heparin preparations and named heparitin sulfate. 4 These names remain in place today and tend to cause some confusion because it is becoming clear that both heparin and heparan sulfate are very closely related and may share many structural and functional activities. The mechanism of action of HS includes specific, noncovalent interaction with various proteins, a process that affects the ultimate fate of the protein, that is, topographical destination, half-life, and bioactivity. The HS roles as co-receptors for various receptor tyrosine kinases and its ability to affect morphogen gradients, and thus development and organogenesis, are important attributes that have raised considerable attention in the past decade. This review focuses on the synthesis and roles of HS in both biology and pathology. It also describes the interactions with various groups of proteins including cytokines and growth factors, which have been shown to be important in controlling the biological activities of the bound factor. It concludes by reviewing the ways in which the structure of HS has been analyzed biochemically and investigated for its possible roles in diseases and pathologies affecting humans.