HLA-G antigens are non classical HLA-class I molecules characterized by a low allelic polymorphism, a limited tissue distribution and the presence of membrane bound and soluble isoforms. The HLA-G antigens were firstly detected in cytotrophoblast cells at the feto-maternal interface where they maintain a tolerogenic status between the mother and the semiallogenic fetus. Recently a variable expression of HLA-G molecules has been documented in several autoimmune diseases, viral infections, cancer diseases and transplantation. Overall the presence of HLA-G molecules in both membranes bound and soluble isoforms was associated with tolerogenic functions against innate and adaptative cellular responses. HLA-G antigens are able to affect the cytotoxicity of natural killer and CD8+ T cells, CD4+ T lymphocyte functions and dendritic cell maturation. In addition to the allelic polymorphism the HLA-G gene shows a deletion/insertion polymorphism of a 14 base pairs sequence (14bp) in the exon 8 at the 3 untranslated region. Several reports have associated the presence of the 14bp insertion allele (+14bp) to an unstable mRNA and a lower sHLA-G protein production, suggesting a different ability to counteract inflammation between genotypes. We reviewed the literature on the expression of HLA-G antigens in autoimmune and allergic diseases and the possible functional role of these molecules in counteracting inflammation.