In humans as in other animal species, CD8⁺ cytotoxic T lymphocytes (CTLs) play an important if not the major role in controlling virus‐infected and malignant cell growth. The interactions between CD8⁺ T cells and target cells are mediated by human leukocyte antigen (HLA) class I antigens loaded with viral and tumor antigen‐derived peptides along with costimulatory receptor/ligand stimuli. Thus, to escape from CD8⁺ T‐cell recognition and destruction, viruses and tumor cells have developed strategies to inhibit the expression and/or function of HLA class I antigens. In contrast, cells with downregulated MHC class I surface expression can be recognized by NK cells, although NK cell‐mediated lysis could be abrogated by the expression of inhibiting NK cell receptors. This review discusses the molecular mechanisms utilized by viruses to inhibit the formation, transport and/or expression of HLA class I antigen/peptide complexes on the cell surface. The knowledge about viral interference with MHC class I antigen presentation is not only crucial to understand the pathogenesis of viral diseases, but contributes also to the design of novel strategies to counteract the escape mechanisms utilized by viruses. These investigations may eventually lead to the development of effective immunotherapies to control viral infections and virus‐associated malignant diseases. © 2005 Wiley‐Liss, Inc.