Heparan sulfate proteoglycans (HSPGs) are glycoproteins found at the cell surface and in the extracellular matrix, where they interact with various ligands. Over the past decade, new insights have emerged regarding the mechanisms and biological significance of these interactions. HSPGs have three main groups: membrane HSPGs, secreted extracellular matrix HSPGs, and secretory vesicle proteoglycans. They play crucial roles in multiple cellular, tissue, and organismal processes, including cell migration, morphogen gradient formation, chemokine signaling, and cell adhesion. HSPGs can bind cytokines, chemokines, growth factors, and morphogens, protecting them from proteolysis and facilitating their activity. They also act as receptors for proteases and protease inhibitors, modulating their spatial distribution and activity. Membrane HSPGs cooperate with integrins and other cell adhesion receptors to facilitate cell-ECM attachment and cell-cell interactions. Additionally, they act as coreceptors for tyrosine kinase-type growth factor receptors, lowering their activation threshold or altering signaling duration. HSPGs can also act as endocytic receptors, facilitating the clearance of bound ligands. The specificity of protein–HSPG binding has been a subject of extensive research, with studies showing that while some ligands bind directly to the HSPG core proteins, most interact with sulfated domains within HSPG chains. The biological functions of HSPGs are regulated by their sulfation patterns and the presence of specific sulfated residues. HSPGs can also act as coreceptors, facilitating the formation and signaling of ligand-receptor complexes, and as endocytic receptors, mediating the internalization of ligands. They play a role in cell adhesion and shape determination, and can regulate growth factor binding to the extracellular matrix and cell migration. HSPGs are also involved in barrier activity, such as maintaining the integrity of the intestinal epithelium and regulating morphogen and chemokine gradients during development. The complex interactions and regulatory roles of HSPGs highlight their importance in various biological processes.Heparan sulfate proteoglycans (HSPGs) are glycoproteins found at the cell surface and in the extracellular matrix, where they interact with various ligands. Over the past decade, new insights have emerged regarding the mechanisms and biological significance of these interactions. HSPGs have three main groups: membrane HSPGs, secreted extracellular matrix HSPGs, and secretory vesicle proteoglycans. They play crucial roles in multiple cellular, tissue, and organismal processes, including cell migration, morphogen gradient formation, chemokine signaling, and cell adhesion. HSPGs can bind cytokines, chemokines, growth factors, and morphogens, protecting them from proteolysis and facilitating their activity. They also act as receptors for proteases and protease inhibitors, modulating their spatial distribution and activity. Membrane HSPGs cooperate with integrins and other cell adhesion receptors to facilitate cell-ECM attachment and cell-cell interactions. Additionally, they act as coreceptors for tyrosine kinase-type growth factor receptors, lowering their activation threshold or altering signaling duration. HSPGs can also act as endocytic receptors, facilitating the clearance of bound ligands. The specificity of protein–HSPG binding has been a subject of extensive research, with studies showing that while some ligands bind directly to the HSPG core proteins, most interact with sulfated domains within HSPG chains. The biological functions of HSPGs are regulated by their sulfation patterns and the presence of specific sulfated residues. HSPGs can also act as coreceptors, facilitating the formation and signaling of ligand-receptor complexes, and as endocytic receptors, mediating the internalization of ligands. They play a role in cell adhesion and shape determination, and can regulate growth factor binding to the extracellular matrix and cell migration. HSPGs are also involved in barrier activity, such as maintaining the integrity of the intestinal epithelium and regulating morphogen and chemokine gradients during development. The complex interactions and regulatory roles of HSPGs highlight their importance in various biological processes.