Heparan sulfate proteoglycans (HSPGs) are found at the cell surface and in the extracellular matrix, where they interact with a wide variety of ligands. Over the past decade, new insights have emerged regarding the mechanisms and biological significance of these interactions. This review discusses changing views on the specificity of protein-HSPG binding and the activity of HSPGs as receptors and coreceptors. Although few in number, HSPGs have profound effects at the cellular, tissue, and organismal levels. HSPGs are glycoproteins containing one or more covalently attached heparan sulfate (HS) chains, a type of glycosaminoglycan (GAG). Cells express a relatively small set of HSPGs, which are divided into three groups based on their location: membrane HSPGs, secreted extracellular matrix HSPGs, and secretory vesicle proteoglycans. Early research focused on the composition, biosynthesis, and binding properties of HS chains. The first somatic cell mutants altered in HSPG expression were identified in 1985, allowing functional studies in cell culture models. Later, HSPG mutants in model organisms such as Drosophila, nematodes, tree frogs, zebrafish, and mice were identified, highlighting the evolutionary conservation of HS. HSPGs participate in various systems, including basement membranes, secretory vesicles, and interactions with cytokines, chemokines, growth factors, and morphogens. They can act as receptors for proteases and protease inhibitors, as coreceptors for growth factor receptors, and as endocytic receptors for ligand clearance. HSPGs also facilitate cell-ECM attachment, cell-cell interactions, and cell motility. The structure and assembly of HSPGs involve complex modifications of HS chains, including sulfation, epimerization, and cleavage by endosulfatases. The binding of ligands to HS follows principles similar to those of other macromolecules, with dissociation constants ranging from millimolar to nanomolar. The specificity of binding is influenced by the sulfation state and arrangement of sulfate groups in HS chains. HSPGs can act as coreceptors for FGF signaling, facilitating the formation of FGF-receptor complexes. They also play a role in trans-activation of signaling between cells, as demonstrated in studies of left-right development in Xenopus. HSPGs are involved in various biological processes, including cell adhesion, barrier function, and morphogen gradient formation. They regulate growth factor binding to the extracellular matrix and cell migration. HSPGs also play a role in maintaining the integrity of the intestinal epithelium and in the regulation of stem cell niches. The interaction of HSPGs with morphogens such as Wg, Hh, and Dpp is essential for their diffusion and gradient formation. HSPGs can modHeparan sulfate proteoglycans (HSPGs) are found at the cell surface and in the extracellular matrix, where they interact with a wide variety of ligands. Over the past decade, new insights have emerged regarding the mechanisms and biological significance of these interactions. This review discusses changing views on the specificity of protein-HSPG binding and the activity of HSPGs as receptors and coreceptors. Although few in number, HSPGs have profound effects at the cellular, tissue, and organismal levels. HSPGs are glycoproteins containing one or more covalently attached heparan sulfate (HS) chains, a type of glycosaminoglycan (GAG). Cells express a relatively small set of HSPGs, which are divided into three groups based on their location: membrane HSPGs, secreted extracellular matrix HSPGs, and secretory vesicle proteoglycans. Early research focused on the composition, biosynthesis, and binding properties of HS chains. The first somatic cell mutants altered in HSPG expression were identified in 1985, allowing functional studies in cell culture models. Later, HSPG mutants in model organisms such as Drosophila, nematodes, tree frogs, zebrafish, and mice were identified, highlighting the evolutionary conservation of HS. HSPGs participate in various systems, including basement membranes, secretory vesicles, and interactions with cytokines, chemokines, growth factors, and morphogens. They can act as receptors for proteases and protease inhibitors, as coreceptors for growth factor receptors, and as endocytic receptors for ligand clearance. HSPGs also facilitate cell-ECM attachment, cell-cell interactions, and cell motility. The structure and assembly of HSPGs involve complex modifications of HS chains, including sulfation, epimerization, and cleavage by endosulfatases. The binding of ligands to HS follows principles similar to those of other macromolecules, with dissociation constants ranging from millimolar to nanomolar. The specificity of binding is influenced by the sulfation state and arrangement of sulfate groups in HS chains. HSPGs can act as coreceptors for FGF signaling, facilitating the formation of FGF-receptor complexes. They also play a role in trans-activation of signaling between cells, as demonstrated in studies of left-right development in Xenopus. HSPGs are involved in various biological processes, including cell adhesion, barrier function, and morphogen gradient formation. They regulate growth factor binding to the extracellular matrix and cell migration. HSPGs also play a role in maintaining the integrity of the intestinal epithelium and in the regulation of stem cell niches. The interaction of HSPGs with morphogens such as Wg, Hh, and Dpp is essential for their diffusion and gradient formation. HSPGs can mod