Natural killer (NK) cells are bone marrow-derived lymphocytes that can kill certain tumor cells and virally infected cells. There are multiple immunoglobulin superfamily (IgSF) receptor-ligand interactions that coordinate NK cell recognition of target cells and cytolytic function. The IgSF receptor NK 2B4 (CD244) is a ligand for CD48 that is expressed on the surface of all mouse and human NK cells and the subset of T cells that mediate NK-like killing. NK 2B4 is a cell surface glycoprotein of the immunoglobulin superfamily that is involved in the regulation of natural killer and T lymphocyte function. NK 2B4 binds the Src homology 2 domain-containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which may function as regulators of NK 2B4-associated signal transduction pathways. NK 2B4 is expressed in human spleen, peripheral blood leukocytes, lymph node, bone marrow and fetal liver.