Lack of expression of major histocompatibility complex (MHC) molecules of both classes is frequently noted on tumour cells . It is thought that in this way tumour cells escape immunosurveillance. The genes encoding both classes of MHC molecules are localized on the distal part of chromosome 6 (6p21.3). The class II transactivator (CIITA), encoded by the MHC2TA gene, is essential for transcriptional activation of all MHC-II genes, while it has a helper function in the transcriptional regulation of MHC-I genes (with the exception of human leukocyte antigen (HLA)-G) and of the gene encoding beta2-microglobulin (beta2m) . Here we discuss our current knowledge on the expression characteristics of MHC2TA and argue for an important role of epigenetic factors and mechanisms in the transcriptional silencing of MHC2TA in cancer cells.