Heparan sulfate (HS) appeared early in metazoan evolution. As such, many of the structural motifs (variably sulfated disaccharide subunits) that characterize HS (and heparin) were established early on and have been preserved in modern organisms. Thus, many of the biological functions associated with HS either occurred early in evolution or have depended on the subsequent evolution of the protein ligands that bind to the polysaccharide. Today, we know of literally hundreds of heparin-binding proteins, and many interactions have profound consequences in vertebrate and invertebrate physiology. This Perspective aims to provide an overview of HS structure, function, and biosynthesis and to set the stage for discussing the relationship between structure and function of these fascinating molecules and how altered HS biosynthesis and catabolism can lead to human disorders.