Heparanase is the only mammalian endo-β-D-glucuronidase known to cleave heparan sulfate (HS) components of proteoglycans(PGs) at limited intra-chain sites. Heparanase release in response to an inflammatory stimulus or in relation to tumor metastasis alters the composition and structural integrity of extracellular matrix and basement membrane. The enzymatic degradation of HS by heparanase is, therefore, involved in range of biological phenomena, from pregnancy, morphogenesis and development to inflammation, vascularization, and cancer progression. In normal physiological processes, expression of the active enzyme is tightly regulated by promoter methylation, mRNA splicing, transcription factors, proteolytic processing and inflammatory cytokines. The recent findings about the strict regulation of heparanase from the expression of the gene to processing of the protein product to yield the active enzyme are reviewed.