The phagocytic function of human-peripheral-blood-derived mononuclear and polymorphonuclear leukocytes can be regulated by external stimuli. In particular, the extracellular matrix (ECM) proteins fibronectin and laminin and serum amyloid P component can increase the phagocytic activity of these cells. Phagocytosis enhancement by the ECM requires two distinct signals to the ingesting cell. First, a ligand for interaction of the target particle with phagocytic cells is required. Generally this occurs because of opsonins such as antibody or complement on the phagocytic target and is independent of the ECM proteins. The phagocytosis-enhancing effect of the connective tissue proteins also requires direct interaction of these proteins with phagocytic cells and occurs through cell surface receptors for these molecules. In the case of neutrophils, sensitivity to the phagocytosis-enhancing effects of connective tissue proteins requires prior stimulation with the chemotactic peptides C5a or f-met-leu-phe. The present state or knowledge of the mechanism of phagocytosis enhancement by ECM proteins and the implications of the phenomenon for host defense are discussed.