Human leukocyte antigen G (HLA-G) is a non classical HLA class I molecule capable to inhibit the allogeneic response (cytotoxicity and proliferation), and through this acts on both innate and adaptive immune cells. During pregnancy, HLA-G plays a fundamental role in foeto-maternal tolerance. This role has been further extended to pathological situations such as transplantation, cancer disease, autoimmunity and viral infections. This review will summarize the immunotolerogenic functions of HLA-G and its involvement in escape mechanisms used by tumor cells. Also will we discuss the expression of HLA-G on primary tumor cells, tumor cell lines, and ascites, and the influence of environmental tumoral factors. All these data strengthen the relevance of HLA-G in cancer and its role in cancer immunoediting. HLA-G may represent one mechanism of tumor-driven immune evasion and thus a powerful therapeutic target.