Heparan sulfate proteoglycans (HSPGs) play vital roles in every step of tumor progression allowing cancer cells to proliferate, escape from immune response, invade neighboring tissues, and metastasize to distal sites away from the primary site. Several cancers including breast, lung, brain, pancreatic, skin, and colorectal cancers show aberrant modulation of several key HS biosynthetic enzymes such as 3-O Sulfotransferase and 6-O Sulfotransferase, and also catabolic enzymes such as HSulf-1, HSulf-2 and heparanase. The resulting tumor specific HS fine structures assist cancer cells to breakdown ECM to spread, misregulate signaling pathways to facilitate their proliferation, promote angiogenesis to receive nutrients, and protect themselves against natural killer cells. This review focuses on the changes in the expression of HS biosynthetic and catabolic enzymes in several cancers, the resulting changes in HS fine structures, and the effects of these tumor specific HS signatures on promoting invasion, proliferation, and metastasis. It is possible to retard tumor progression by modulating the deregulated biosynthetic and catabolic pathways of HS chains through novel chemical biology approaches.