The crucial role played by human leukocyte antigen (HLA) antigens and natural killer (NK)-cell-activating ligands in the interactions of malignant cells with components of the host's immune system has stimulated interest in the characterization of their expression by malignant cells. Convincing evidence generated by the immunohistochemical staining of surgically removed malignant lesions with monoclonal antibodies recognizing HLA antigens and NK-cell-activating ligands indicates that the surface expression of these molecules is frequently altered on malignant cells. These changes appear to have clinical significance because in some types of malignant disease they are associated with the histopathological characteristics of the lesions as well as with disease-free interval and survival. These associations have been suggested to reflect the effect of HLA antigen and NK-cell-activating ligand abnormalities on the interactions of tumor cells with antigen-specific cytotoxic T lymphocytes (CTL) and with NK cells. Nevertheless, there are examples in which disease progresses in the face of appropriate HLA antigen and/or NK-cell-activating ligand as well as tumor antigen expression by malignant cells and of functional antigen-specific CTL in the investigated patient. In such scenarios, it is likely that the tumor microenvironment is unfavorable for CTL and NK cell activity and contributes to tumor immune escape. Many distinct escape mechanisms have been shown to protect malignant cells from immune recognition and destruction in the tumor microenvironment. In this article, following the description of the structural and functional characteristics of soluble HLA antigens and NK-cell-activating ligands, we will review changes in their serum level in malignant disease and discuss their potential role in the escape mechanisms used by tumor cells to avoid recognition and destruction.