Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. In many malignancies, high heparanase expression and activity correlate with an aggressive tumour phenotype. A major consequence of heparanase action in cancer is a robust up-regulation of growth factor expression and increased shedding of syndecan-1 (a transmembrane heparan sulfate proteoglycan). Substantial evidence indicates that heparanase and syndecan-1 work together to drive growth factor signalling and regulate cell behaviours that enhance tumour growth, dissemination, angiogenesis and osteolysis. Preclinical and clinical studies have demonstrated that therapies targeting the heparanase/syndecan-1 axis hold promise for blocking the aggressive behaviour of cancer. Levels of the heparan sulfate proteoglycan syndecan-1 and the heparan sulfate degrading enzyme heparanase are elevated in many cancers. Together these two molecules form a powerful axis that promotes an aggressive tumor phenotype. This review focuses on the mechanism of action of the heparanase/syndecan-1 axis and emerging therapeutic strategies to target this axis. © 2013 The Authors Journal compilation © 2013 FEBS.