The Human Leukocyte Antigen G (HLA-G) is a non-classical class I MHC which is characterized by low polymorphism at the DNA level, limited tissue distribution in non-pathological conditions and the expression of both membrane-bound and soluble isoforms by alternative splicing. This molecule has become the object of interest because of its possible role in pregnancy maintenance. HLA-G seems to be involved in the induction and maintenance of tolerance between the mother immune system and the semi-allogeneic fetus at the fetal-placentary interface, and also seems to play an important role in embryo implantation. Besides, several studies point out to a broader immunoregulatory role for this molecule. Here we review the potential roles of the HLA-G molecule on the immune system, the unique regulatory region of its gene, the influence of gene polymorphisms on HLA-G expression, as well as several situations in which this molecule has been involved, such as pregnancy, transplantation, cancer, viral infections and, more recently, inflammatory diseases.