Changes in classical and nonclassical HLA class I antigen and NK cell-activating ligand expression have been identified in malignant lesions. These changes, which are described in this chapter, are believed to play a major role in the clinical course of the disease since both HLA class I antigens and NK cell-activating ligands are critical to the interaction between tumor cells and components of both innate and adaptive immune systems. Nevertheless, there is still debate in the literature about the biologic and functional significance of HLA class I antigen and NK cell-activating ligand abnormalities in malignant lesions. The reasons for this debate are reviewed. They include (i) the incomplete association between classical HLA class I antigen changes and the clinical course of the disease; (ii) the relatively limited number of malignant lesions that have been analyzed for nonclassical HLA class I antigen and NK cell-activating ligand expression; and (iii) the conflicting data regarding the role of immunoselection in the generation of malignant cells with HLA antigen and NK cell-activating ligand abnormalities. The technical limitations associated with the assessment of HLA antigen and NK cell-activating ligand expression in malignant lesions as well as the immunological and nonimmunological variables that may confound the impact of HLA antigen and NK cell-activating ligand changes on the clinical course of the disease are also discussed. Future studies aimed at overcoming these limitations and characterizing these variables are expected to provide a solution to the current debate regarding the significance of HLA class I antigen and NK cell-activating ligand abnormalities in malignant lesions.