Heparanase activity is strongly implicated in structural remodeling of the extracellular matrix, a process which can lead to invasion by tumor cells. In addition, heparanase augments signaling cascades leading to enhanced phosphorylation of selected protein kinases and increased gene transcription associated with aggressive tumor progression. This function is apparently independent of heparan sulfate and enzyme activity, and is mediated by a novel protein domain localized at the heparanase C-terminus. Moreover, the functional repertoire of heparanase is expanded by its regulation of syndecan clustering, shedding, and mitogen binding. Recent reports indicate that modified glycol-split heparin, which inhibits heparanase activity, can profoundly inhibit the progression of tumor xenografts produced by myeloma and carcinoma cells, thus moving anti-heparanase therapy closer to reality. © 2009 Elsevier Ltd. All rights reserved.