Signaling by growth factors is finely balanced to ensure normal tissue homeostasis while avoiding abnormal neoplastic growth. Cell surface proteoglycans are strategically positioned to bind growth factors and their receptors and regulate their intracellular signaling events by acting as mandatory co-receptors. Intense research in the area of glycobiology reveals important roles for proteoglycans in neoplastic growth and cancer as a result of their interaction with growth factors and growth factor receptors. Our research focuses on understanding the regulatory role of proteoglycans and glycosaminoglycans in growth factor signaling within the tumor microenvironment. Proteoglycans are proteins substituted with polyanionic carbohydrate chains called glycosaminoglycans. The variable length of glycosaminoglycan chains together with detailed structural modifications result in extensive diversity and thereby various effects on growth factor signaling. We investigate the role of proteoglycans and their glycosaminoglycan chains in neoplastic behavior by studying their structural biology, growth factor signaling pathways, effects on gene and protein expressions as well as their effects on tumor growth and tumor metastasis using different in vitro and in vivo tumor models.