Opsonin-independent phagocytosis, mediated by direct recognition of micro-organisms and particulate matter by cell surface receptors, is an important host defense mechanism, and also a potential means for pathogen entry into cells. Among the receptors currently known to mediate opsonin-independent phagocytosis the best characterized is the macrophage scavenger receptor. These receptors, which exhibit multiple ligand specificities, mediate opsonin-independent phagocytosis of microorganisms and also bind modified lipids. Additional receptor systems can mediate opsonin-independent phagocytosis. These include scavenger-type receptors which are also involved in binding of inhaled environmental particles by lung macrophages. Further identification and characterization of receptors that mediate opsonin-independent phagocytosis should lead to a better understanding of this important process in natural immunity.