The polyanionic linear polysaccharide heparan sulfate specifically interacts with a multitude of extracellular ligands relevant to all steps of tumor progression. Heparan sulfate proteoglycans act as coreceptors for cytokine and chemokine signaling, modulating tumor cell growth and survival, chemotaxis, and angiogenesis. As matrix receptors, they act in concert with integrins to regulate tumor cell motility. As binding partners for matrix metalloproteinases and protease inhibitors, they regulate the proteolytic microenvironment of tumors, thus modulating metastatic spread. Processing enzymes such as heparanase and HSulf-1 and HSulf-2 can further modify the biochemical properties of heparan sulfate and promote tumor progression. As dysregulated expression of heparan sulfate proteoglycans and heparan sulfate-processing enzymes has been observed in numerous tumor entities, the development of glycan-based drugs targeting their biological functions has become an area of intense research. Promising results have been obtained both in animal models and in phase I–III clinical trials.