After the completion of the human genome, a need was identified by scientists to look for a functional map of the human genome. Epigenomics provided functional characteristics of genes identified in the genome. Epigenetics is the alteration in gene expression (function) without changing the nucleotide sequence. Both activation and inactivation of cancer-associated genes can occur by epigenetic mechanisms. The major players in epigenetic mechanisms of gene regulation are DNA methylation, histone deacetylation, chromatin remodeling, small noncoding RNA expression and gene imprinting. In the last few years, epigenetic mechanisms have been studied in a number of tumor types and epigenetic markers have been identified that are suitable for cancer detection, diagnosis, follow-up of treatment and screening high-risk populations. One interesting aspect of epigenetics is the reactivation of genes by successful reversion of some epigenetic changes using chemicals. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to the reactivation of silenced genes. In this article, we have described the current status of this powerful science and discussed the challenges in the clinical fields where epigenetic approaches in cancer are applied.