Convincing clinical evidence indicates that the limited success of T-cell-based immunotherapy of malignant diseases is caused, at least in part, by the ability of malignant cells to escape from immune recognition and destruction. Among the multiple escape mechanisms identified, a major role is played by changes in the expression and/or function of HLA antigens expressed by tumor cells, because they may markedly affect tumor cell-host's immune system interactions. In this article, we review the data about the aberrant expression of the nonclassical HLA class I antigen HLA-G by tumor cells. Furthermore, we discuss the possible reasons for the conflicting information in the literature about HLA-G antigen expression by malignant cells. Lastly, in light of the well-documented immunotolerant function of HLA-G, we discuss the potential role of these antigens in the escape of tumor cells from immune recognition and destruction and in the clinical course of malignant diseases.