Over the past few years, the number of publications concerning the human leukocyte antigen (HLA)-G molecule, its functions, and its pathological implications has greatly increased, largely exceeding those focusing simply on fetal-maternal activity. The role of this molecule in other situations of tolerance such as transplantation, tumor dissemination, or virus infections has also been reported. In this paper, we focus our attention on the relevance of HLA-G in transplantation in the light of recent data associating regulatory T cells and HLA-G, and which provide evidence of the role of HLA-G in improving graft acceptance.