HLA-G (Human Leucocyte Antigen-G) is a non-classical HLA class I molecule observed for the first time in human cytotrophoblast. Numbers of investigations have demonstrated that HLA-G was broader than originally thought. In fact, it is expressed in pathological contexts as well as in physiological contexts. This expression of HLA-G and its receptors in immunity cells confer to it a major role in immune responses. Good issues were described in organ transplantation when HLA-G was expressed. But, HLA-G transcripts and/or proteins expression in tumor tissues was associated with tumor genesis and cancer progression. A focus on the expression and the role of HLA-G in tumor context will be developed in this review. In addition, regulation of HLA-G will be treated to improve strategies of cancer therapy.