This review describes recent advances in understanding how epigenetic events control MHC-class-II-family (MHC-II) gene expression. To address this issue, two phases of gene transcription have to be considered. First, the control of MHC-II by chromatin-modifying events such as histone acetylation, methylation, deacetylation, ubiquitination and the interplay between these different epigenetic events will be examined. The interactions of chromatin-modifying enzymes with class II transactivator (CIITA) and relevant DNA-binding proteins for activating and silencing MHC-II gene transcription will be reviewed. Second, the transcriptional control of the promoter of CIITA, the master regulator of MHC-II, by DNA methylation and chromatin modification will be discussed, and the novel role of noncoding RNA will be explored. Finally, the relevance of these findings to infection, transplantation and cancer will be reviewed.