The observation that cancer cells suffer profound alterations in the DNA methylation profile, with functional consequences in the activity of key genes, together with the recognition that epigenetic alterations might be as important as genetic defects in the origin of cancers has started a new era in cancer research. In a few years, key discoveries have abruptly changed our vision of the determinants of cancer. Breakthroughs in the cancer epigenetics field include the finding of a tumor-type specificity of genes that suffer epigenetic deregulation at both DNA methylation and histone modifications, the interconnection between different epigenetic marks, the identification of mechanisms of targeting of epigenetic alterations, including the participation of Polycomb group (PcG) proteins, or the involvement of small RNAs, which regulate hundreds of target genes. All these findings have multiple implications: first, they shed light on the mechanistic insights by which epigenetic defects complement genetic alterations in the development and progression of cancer; second, epigenetic alterations appear to play a prominent role in the initiation of cancer. In addition, because epigenetic changes are reversible, enzymes involved in their maintenance stand as targets for a variety of compounds for therapy.