Cellular interactions during blood-borne transport of malignant cells, including the interactions of tumor cells with themselves, platelets, lymphocytes, blood components, and the vascular endothelium, can play important roles in metastasis formation. Since blood-borne metastasis often occurs to specific organ sites in vivo, recognition must occur between the circulating malignant cells and the vascular endothelium. We have used vascular endothelial cells and their underlying basal lamina-like matrix as targets for tumor cell interactions. Our findings indicate that highly metastatic tumor cells attach more rapidly and avidly to the endothelial basal lamina-like matrix than to the apical surfaces of the endothelial cells. Since the former contains cell adhesive molecules such as fibronectin and laminin, these molecules, as well as collagens and proteoglycans, may be collectively responsible for the higher rates of malignant cell binding to the basal lamina. Glycoproteins present on malignant cell surfaces are also important in these interactions, because inhibiting their biosynthesis with tunicamycin blocks blood-borne implantation and experimental metastasis formation and prevents malignant cell binding to endothelial cells or their basal lamina-like matrix. Invasion of blood vessel walls requires that malignant cells penetrate the endothelial cell layer and underlying basal lamina. Metastatic cells appear to perform these activities using degradative enzymes such as proteases and glycosidases that solubilize the major basal lamina components: glycoproteins, collagens, and proteoglycans. We have examined the degradation of basal lamina proteoglycan side chain glycosaminoglycans using purified tissue glycosaminoglycans as substrates. B16 melanoma cells of high organ colonization capacities possess higher levels of endoglycosidase activity against heparan sulfate than B16 cells of lower organ colonization potentials. The highly malignant B16 cells were capable of cleaving the heparan sulfate molecules at specific intrachain glucuronoside sites, producing intermediate molecular weight products.