The recognition of epigenetic defects in all types of cancer has represented a revolutionary achievement in cancer research in recent years. DNA methylation aberrant changes (global hypomethylation and CpG island hypermethylation) were among the first events to be recognized. The overall scenario comprises a network of factors in which deregulation of DNA methyltransferases leads to a cancer-type specific profile of tumor suppressor genes that become epigenetically silenced. Over recent years, a better understanding of the machinery that connects DNA methylation, chromatin and transcriptional activity, in which histone modifications stand in a key position, has been achieved. The identification of these connections has contributed not only to understanding how epigenetic deregulation occurs in cancer but also to developing novel therapies that can reverse epigenetic defects in cancer cells.