Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.