Regulatory cells play a crucial role in the maintenance of the immune homeostasis and in pathologic conditions such as those involving transplantations, autoimmune diseases, infections, and cancers. The regulatory cells block the function of other effector cells and can induce the formation of other regulatory cells. Human leukocyte antigen (HLA)-G is a nonclassic class I molecule that functions as an immune-tolerogenic molecule with restricted tissue expression. Numerous studies have highlighted the role of HLA-G in the context of transplantation, cancer, autoimmunity, and hematologic diseases. HLA-G has a direct inhibitory effect on immune responses but there is increasing evidence that it also has a long term immunomodulatory effect and can induce the generation of suppressor/regulatory cells. In this article we review the different natures, functions, and significance of the various types of HLA-G-dependent suppressor cells.