Signaling co-receptors are diverse, multifunctional components of most major signaling pathways, with roles in mediating and regulating signaling in both physiological and pathophysiological circumstances. Many of these signaling co-receptors, including CD44, glypicans, neuropilins, syndecans and TssRIII/betaglycan are also proteoglycans. Like other co-receptors, these proteoglycan signaling co-receptors can bind multiple ligands, promoting the formation of receptor signaling complexes and regulating signaling at the cell surface. The proteoglycan signaling co-receptors can also function as structural molecules to regulate adhesion, cell migration, morphogenesis and differentiation. Through a balance of these signaling and structural roles, proteoglycan signaling co-receptors can have either tumor promoting or tumor suppressing functions. Defining the role and mechanism of action of these proteoglycan signaling co-receptors should enable more effective targeting of these co-receptors and their respective pathways for the treatment of human disease.