Following a description of the way studies of human leukocyte antigen (HLA) class I antigen expression by tumor cells have evolved through the years, the literature related to the frequency of defects in HLA class I antigen processing machinery (APM) component expression in various types of malignancies is reviewed. In addition, the clinical significance of defects in HLA class I APM components as well as the underlying molecular mechanisms are described. Lastly, potential strategies to overcome the defects in HLAclass I APM component expression and function are discussed. The information presented indicates a revival of the interest in the characterization of HLA class I APM component expression by tumor cells since these molecules may play an important role in the outcome of immunotherapy with inhibitory checkpoint molecule-specific monoclonal antibodies in patients with malignant disease. Furthermore, they may represent a useful prognostic biomarker to select patients who might benefit from these types of immunotherapy.