A growing interest around heparanase and its role in cancer, inflammation and other diseases prompted the identification of specific inhibitors of this enzyme and the exploration of their potential therapeutic role. Roneparstat, a 15-25 kDa N-acetylated and glycol split heparin, is one of the most potent and widely studied heparanase inhibitors. These studies generated a large body of data, which allowed to characterize Roneparstat properties and to endorse its potential therapeutic role. Multiple Myeloma represents the indication that most of the studies, including the phase I clinical trial, addressed. However, Roneparstat antitumor activity activity has been documented in other cancers, and in non-oncological conditions.In addition, assessing Roneparstat activity in different experimental models contributed to understanding heparanase role and the biological factors that may be affected by heparanase inhibition in more detail. Finally, some studies elucidated the molecular mechanisms regulating the enzyme-inhibitor kinetics, thus providing important data for the identification and design of new inhibitors.The objective of this chapter is to provide a comprehensive overview of the most significant studies involving Roneparstat and discuss its potential role in therapy.