CD200 is a widely distributed membrane glycoprotein that regulates myeloid cell activity through its interaction with an inhibitory receptor (CD200R). The interaction is of interest as a target for treating excessive inflammation and for treating leukemia. There are closely related proteins to CD200R that give activating signals making this a “paired receptor.” We report X-ray crystallography structures for the inhibitory CD200R, the activating receptor CD200RLa, and a complex between CD200R and CD200. Both CD200 and CD200R contain two Ig-like domains and interact through their NH2 terminal domains compatible with immunological synapse-like interactions occurring between myeloid cells and other CD200-expressing cells. The failure of the activating receptor to bind CD200 resides in subtle changes around the interface. CD200 has been acquired by herpes viruses to mimic the host interaction. CD200R has evolved rapidly presumably driven by pathogen pressure but it may also be important in homeostasis through interactions with commensal bacteria. •Structure of CD200R and in complex with its ligand CD200 complex•Structure of an activating member of the CD200 receptor family•Mutagenesis showing specificity of CD200 paired receptor family Hatherley et al. present a structural basis explaining why the cell surface protein CD200 binds to its receptor (CD200R) but not to the related activating receptor CD200RLa. The rapid evolution of the receptors was probably driven by pathogens and might play a role in mediating interaction with the microbiome.