Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule that has tolerogenic functions and acts on cells of both innate and adaptive immunity. The molecular mechanism leading to tolerance involves the interaction between HLA-G and inhibitory receptors that are expressed at the surface of immune cells. In this review, we will briefly summarize the key advances on the relationships between HLA-G and the immune system and their consequences in pathology.