Alterations in the MHC class I surface antigens represent one mechanism of tumor cells to escape from natural or immunotherapy-induced antitumor immune responses. In order to restore MHC class I expression, knowledge about the underlying molecular mechanisms of MHC class I defects in different tumor types is required. In most cases, abnormalities of MHC class I expression are reversible by cytokines suggesting a deregulation rather than structural abnormalities of members of the antigen-processing and presentation machinery (APM). The impaired expression of APM components could be controlled at the epigenetic, transcriptional and/or posttranscriptional level. Furthermore, a direct link between altered transcription factor binding, interferon signal transduction and MHC class I APM component expression has been shown, which might be further associated with cell cycle progression. This information will not only give novel insights into the (patho) physiology of the antigen-processing and presenting pathway, but will help in the future to design effective T cell-based immunotherapies.