As its discovery nears a half century, the widespread use of F4/80 antigen as a differentiation marker of tissue macrophages of the mouse, continues to raise questions in and beyond experimental cellular immunology. Its structure as a 7 transmembrane G Protein-Coupled Receptor initiated the discovery of a diverse family of plasma membrane receptors. This review will trace milestones of research into the expression of F4/80, also known as Emr1, its value as a marker in formulation of the Mononuclear Phagocyte System and its function in a model of peripheral immune tolerance in the anterior chamber of the eye. Human EMR1 is closely related to a primate-restricted myeloid mechanoreceptor, EMR2, with a novel autocatalytic activation mechanism. We describe their relation to structurally related members of the group E adhesion GPCR subfamily and their contributions to homeostatic systems of the body through local plasma membrane cellular interactions.