Leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) is a member of leukocyte Ig-like receptors (LILRs), also known as CD85D, ILT4, LIR2, and MIR10, contains four extracellular immunoglobulin domains, a transmembrane domain, and three cytoplasmic ITIMs. It is expressed on hematopoietic stem cells, monocytes, macrophages, DCs, neutrophils, basophils, platelets, and activated CD4+T cells, as well as in vitro cultured endothelial cells, mast cell progenitors, and osteoclasts. LILRB2 plays physiological roles in multiple tissues. LILRB2 is involved in immunotolerance in pregnancy and transplantation. HLA-G/LILRB2 interactions promote accumulation and the suppressive activity of MDSCs during human pregnancies. Crosslinking of LILRB2 with Fcγ R in vitro led to inhibition of Fcγ R-mediated signaling in monocytes and serotonin release in basophilic cells. Upregulation of LILRB2 induced the tolerance of DCs. Interaction of LILRB2 with HLA class I molecules is positively associated with viral replication in HIV, suggesting that this interaction leads to a blunted immune response. Upregulation of LILRB2 and LILRB4 in antigen-presenting cells in response to Salmonella infection suggests a role for these receptors in balancing the inflammatory response against bacterial infection. LILRB2 is localized in neutrophil lipid rafts and rapidly moves to the cell surface upon neutrophil stimulation. This upregulated LILRB2 then enhances the inhibitory signals of HLAG on the phagocytic function of neutrophils. Future studies are required to shed light on how neutrophil and immune responses are modulated through LILRB2 interactions with this diverse set of ligands.