This article focuses on the emerging views and concepts concerning the role of cell surface and extracellular heparan sulfate-like glycosaminoglycans (HSGAGs) in tumor biology. HSGAGs, found ubiquitously both at the cell surface and in the extracellular matrix (ECM), play a critical role in regulating tumor initiation, progression, and metastasis. The diverse biological functions of HSGAGs include the regulation of coagulation, growth factor signaling, cell adhesion, proliferation, and mobility. HSGAGs, depending on their location (anchored at the cell surface or soluble as free GAGs), the signaling molecules they associate with, and their fine structures, can either promote or inhibit the tumorigenic process.