Heparanase inhibition represents a new and interesting target for addressing cancer as well as other inflammatory-based diseases. This target is still largely underexploited. Heparanase activity releases from the extracellular matrix (ECM) and tumor microenvironment a multitude of heparan sulphate (HS)-bound growth factors, cytokines, chemokines, and enzymes that affect cells and tissue functions such as inflammation, wound healing and tumor invasion. A pro-metastatic and pro-angiogenic role for this enzyme has been widely demonstrated in many primary human tumors since high levels of heparanase correlate with lymph node and distant metastasis, elevated microvessel density and reduced survival of cancer patients. Heparanase is up regulated in many human hematologic and solid tumors. Two HS mimetics, PG545 and Roneparstat, are in active clinical development, the former in solid tumors, and the latter in Multiple Myeloma (MM). These progresses together with increasing and sound preclinical data suggesting a significant potential for anti-heparanase therapy in many types of tumors, underscores the need to explore the full potential of this novel and safe therapeutic approach. This paper reviews the role of heparanase as novel therapeutic target in cancer and illustrates Roneparstat as a concrete example of such potential.