Fibronectins are widespread extracellular matrix and body fluid glycoproteins, capable of multiple interactions with cell surfaces and other matrix components. Their structure at a molecular level has been resolved, yet there are still many unanswered questions regarding their biologic activity in vivo. Much data suggests that fibronectins may promote extracellular matrix assembly, and cell adhesion to those matrices. However, one outstanding enigma is that fibronectins may, under different circumstances, promote both cell migration and anchorage. An analysis of the interaction of fibroblasts with proteolytically derived and purified domains of plasma fibronectin revealed that the type of adhesion and the correlated cytoskeletal organization depended on multiple interactions of fibronectin domains with the cell surface. Human dermal fibroblasts were capable of interacting with the integrin-binding domain and both heparin-binding domains of the plasma fibronectin molecule and their interactions determined the type of adhesion. The same principle was seen in a study of the ability of plasma fibronectin to promote basement membrane assembly in an endodermal cell line, PF-HR9. There also, interactions of both heparin- and integrin-binding domains combined to promote the deposition of a proteoglycan, laminin, and type IV collagen-containing basement membrane matrix. The underlying conclusion from our studies is, therefore, that fibronectins may, through their different isotypes, multiple receptors, and varying interaction of one or more domains with those receptors, result in a spectrum of responses in different cell types. The molecular details of this array of biologic activities is not resolved but is the target of much current research.