Recent analyses demonstrate that the three receptor protein-tyrosine kinases of the Tyro 3 family function as central regulators of the activation state of macrophages. These studies, carried out in cells and tissues derived from single, double and triple mouse knockouts, have shown that Tyro 3 family receptors limit the magnitude and extent of macrophage activation subsequent to an initial immune stimulus. In the absence of this signaling system, macrophages are constitutively activated. This, in turn, results in a hyperactivated immune system, lymphoproliferation, the development of autoimmunity and early death.