Novel therapeutic strategies such as the modulation of dendritic cell and T-cell function have exhibited great potential in clinical transplantation. Human leukocyte antigen (HLA)-G is a molecule that plays a significant role in establishing complex mechanisms to protect semiallogeneic fetuses from rejection by the maternal immune system. The unique characteristics of both cell-surface and soluble isoforms of HLA-G, the formation of disulfide-bonded dimers with the potential to augment inhibitory receptor signaling, and the function of HLA-G as a preferential ligand for the immunoglobulin-like transcript receptors make HLA-G very important in fundamental approaches for the modulation of immune responses to improve allogeneic graft survival in clinical transplantation. Experimental data from several groups as well as our data from experiments involving HLA-G-mediated human tolerogenic dendritic cells in vitro and receptor transgenic mice in vivo indicate that different isoforms of HLA-G have various immunomodulatory effects through the inhibitory receptors. This knowledge is crucial in understanding mechanisms of prolongation of allograft survival. The analyses of HLA-G isoforms and inhibitory receptors in patients with kidney allograft and the relationship among different isoforms of HLA-G, inhibitory receptors, their mediated immunoregulation, and graft acceptance or failure will be discussed here.