The description of healthy individuals homozygous for the human leukocyte antigen-G (HLA-G) null allele raised doubts about the role of HLA-G in fetal-maternal tolerance. In light of recent results, we discuss this point by considering the potential activity of this null allele that might, indeed, produce functional truncated HLA-G molecules. In this context, we have recently described that, like the full-length HLA-G1, the HLA-G2, -G3, and -G4 truncated isoforms may be expressed at the cell surface and may modulate both innate and acquired immune responses.