Siglecs (sialic acid binding Ig-like lectins) are I-type (Ig-type) lectins belonging to the Ig superfamily. They are characterized by an N-terminal Ig-like V-type domain which mediates sialic acid binding, followed by varying numbers of Ig-like C2-type domains. Siglec-2 (CD22) belongs to a family of immune inhibitory Siglecs, which bears ITIM to deliver immunosuppressive signals such as reduced phagocytosis, dampened inflammation, and inhibited danger-associated molecular pattern/ pathogen-associated molecular pattern (DAMP/PAMP)-mediated inflammation. Siglec-2 is a cell surface receptor expressed mostly on B cells that regulates B-cell proliferation, survival, signaling, and antibody production. The structure of Siglec-2 contains six tyrosines in its cytoplasmic tail, four of which are in ITIM motifs: Y783, Y843, Y863, and Y828. Following cross-linking of B-cell receptors (BCRs), these tyrosine residues are phosphorylated and recruit Src homology region 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1), which dephosphorylates BCR-proximal signaling complexes. Siglec-2 is an attractive therapeutic target considering its unique presence in B lymphocytes. Currently, many ongoing trials evaluating CD22-directed chimeric antigen receptors (CARs), particularly in children with relapsed or refractory B-cell leukemia, are showing safety and efficacy. Some novel CARs, such as bispecific CD20/CD22 CARs and CD19/CD22 CARs, are also in development.