Despite a number of controversies, the functional importance of human leukocyte antigen G (HLA‑G) in early human pregnancy is now sustained by a large amount of sound data. Membrane‑bound and soluble HLA‑G isoforms, either as b2‑microglobulin–free or–associated as monomers or dimers, are expressed by different trophoblast subpopulations, the only fetal‑derived cells that are directly in contact with maternal cells (maternal–fetal interfaces). Trophoblast HLA‑G is the specific ligand of multiple cellular receptors present in maternal immune and non‑immune cells, including CD8, leukocyte immunoglobulin‑like receptor (LILR) B1, LILRB2, killer cell immunoglobulin‑like receptor (KIR) 2DL4, and possibly CD160. Trophoblast HLA‑G specific engagement of these cellular receptors triggers either inhibitory or activating signals in decidual CD8+ T cells, CD4+ T cells, natural killer (NK) cells, macrophages, dendritic cells, or endothelial cells. Such HLA‑G–receptor specific interactions first contribute to limit potentially harmful maternal anti‑paternal immune response by impairment of decidual NK cell cytotoxicity, inhibition of CD4+ and CD8+ T‑cell and B‑cell proliferation, and induction of apoptosis of activated CD8+ T cells. Second, these HLA‑G specific interactions contribute to stimulate placental development through secretion of angiogenic factors by decidual NK cells and macrophages, and to provide a protective effect for the outcome of pregnancy by the secretion of interleukin (IL)‑4 by decidual trophoblast antigen‑specific CD4+ T cells.(Biomed J 2015; 38: 32‑38)