The sulfated domains of HS are the main regions involved in the recognition of growth factors and other proteins. They are separated by flexible spacers of low sulfation. Although there is a vast potential for sequence diversity in the S-domains, the variation in any one cell type may be restricted as a result of the substrate specificities of the polymer-modifying enzymes that convert the precursor heparan (GlcA-GlcNAc) n to HS. Several proteins will bind to any individual S-domain, often by recognizing different structural features of the domain. Minimal sequences designed for binding exclusively to one protein are predicted to be rare but of major importance in cell biology. Evidence from animals deficient in HS-biosynthetic enzymes suggests that weak GAG-protein interactions may be more significant than was previously realized, and this has implications for understanding the mode of action of HS and for the design of HS/heparin mimetics.