Human leukocyte antigen G (HLA-G) is a nonclassic major histocompatibility complex (MHC) class I molecule that functions as an immunomodulatory molecule capable of protecting fetal tissues from the maternal immune system. The relevance of HLA-G in other contexts was investigated soon afterward. Numerous studies have sought (and some have shown) the relevance of HLA-G in pathologic conditions, such as transplantation, autoimmunity, and cancer and hematologic malignancies. One of the main goals of the current research on HLA-G is now to use it in the clinic, either for diagnosis or as a therapeutic tool/target. For this, precise knowledge on the nature and functions of HLA-G is critical. We highlight here what we consider are recent key basic findings on the immunomodulatory function of HLA-G. These strengthen the case for considering HLA-G as clinically relevant.