Heparan sulfate proteoglycans (HSPGs) are widely distributed in mammalian tissues and involved in a number of processes related to malignancy. They are composed of a core protein to which chains of the glycosaminoglycan, heparan sulfate (HS), are attached. The existence of various classes of core protein, in addition to highly polymorphic HS chains, creates a superfamily of macromolecules with considerable diversity of structure and function. HSPGs interact with many proteins including growth factors, chemokines and structural proteins of the extracellular matrix to influence cell growth, differentiation, and the cellular response to the environment. The recent identification of two inherited syndromes that are associated with an increased cancer risk, and caused by mutations in HSPG-related genes, has intensified interest in these molecules. This review describes our current understanding of HSPGs in cancer and highlights new possibilities for therapeutic control.