CD200R1, also known as OX-2 receptor, is an Ig superfamily transmembrane glycoprotein found in myeloid cells and also can be induced in certain T-cell subsets. CD200R1 is composed of a 215 amino acid extracellular domain, a 21 amino acid transmembrane segment, and a 61 amino acid cytoplasmic domain. CD200R1 interacts with CD200 which is also an Ig superfamily transmembrane glycoprotein to downregulate myeloid cell functions. The CD200R1 extracellular domain contains two IgSF domains and the cytoplasmic domain contains three tyrosine residues, one of which forms part of an NPXY motif. CD200R1 expression is restricted primarily to mast cells, basophils, macrophages, and dendritic cells, which suggests myeloid cell regulation as the major function of the CD200:CD200R1 axis. CD200 and CD200R interact with each other through N-terminal IgSF domains. Their interaction plays important roles in negatively regulating immune responses, and attenuating autoimmune diseases and excessive inflammatory responses against pathogens. High expression of CD200 in the CNS is thought to be a mechanism of constitutive immune suppression, and is developmentally regulated in the mouse brain. Deficiency in neuronal CD200 may explain the chronic inflammation in human neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis. The CD200 and CD200R interaction has also been shown to play an important role in the regulation of anti-tumor immunity, and overexpression of CD200 has been reported in a number of malignancies, including CLL, as well as on cancer stem cells.