The CD5 coreceptor is a cysteine-rich scavenger receptor family glycoprotein that is expressed constitutively on all T cells and a subset of B cells (B1a B cells). It is now generally accepted that the biologic role of CD5 is to regulate intracellular strength induced by antigen receptors in both T and B cells. However, at present it is unclear if this coreceptor's effect on antigen receptor signaling is primarily costimulatory or inhibitory since support for both exists. Our studies focus on understanding the physiologic role of CD5 in the context of regulation of antigen receptor activation, B and T cell selection, and generation/maintenance of immune tolerance. In this overview, I discuss studies using experimental models of lymphocyte selection and tolerance showing that CD5 plays a key role in B and T cell selection as well as generation and maintenance of tolerance. I and others, reviewed here, now provide clear evidence that CD5 is a key regulator of immune tolerance and that alterations of its activity can promote development of autoreactivity.