The relevance of the nonclassical human leukocyte antigen (HLA) class I molecule HLA-G in human physiological and pathological contexts has been the center of intense investigation. In light of the recent advances, we report here the clinical implications of HLA-G as a tolerogenic molecule promoting uterine implantation of the embryo or acceptance of solid allografts while allowing the evasion of tumors or viruses from the immune response. These recent findings are important in terms of clinical benefits at both diagnostic and therapeutic levels.