The expression of HLA-G in cancer represents a strategy employed by tumors to avoid immune destruction. Indeed, this non-classical HLA class I molecule suppresses various immune cell functions through binding to inhibitory receptors. We here review the studies done by our group that described for the first time (i) HLA-G expression in malignancies such as melanomas, renal and breast carcinomas. (ii) the up-regulation of HLA-G gene transcription by tumor environmental factors such as cytokines and stress and by agents used in chemotherapy such as demethylating molecules, and (iii) the biological relevance of such HLA-G expression in the evasion of malignant cells from antitumor immune response.