A diverse array of cell surface receptors is known to control immune function, reflecting the integration of positive and negative signaling. Many receptors with opposing functions are isoforms of molecules with similar extracellular domains and different intracellular signaling cytoplasmic domains. The receptor(s) for the relatively ubiquitously expressed cell-surface molecule CD200 (previously referred to as OX2), CD200R(s) is one example of such paired receptors, a feature confirmed by structural and functional analysis. Expression of CD200Rs is most apparent in tissues of myeloid/macrophage origin, although some expression on lymphoid cells has also been documented. This review discusses new data in the field, and the evidence that agonists/antagonists of CD200 or the different CD200Rs might contribute to the treatment of numerous diseases, including allergy, autoimmunity, transplantation and cancer.