DNA in the nucleus of eukaryote cells is packaged in the nucleosomes around histone proteins, and this is highly organized and tightly regulated to control gene transcription. This packaging is not static and the histone tails undergo a wide variety of post-translational modifications that regulate gene transcription, and these patterns have been shown to be aberrantly regulated in multiple disease states. The biology behind these histone modifications is being elucidated, and it is now known that multiple proteins control the writing, reading and removal of these covalent histone modifications. The first agents, vorinostat and romidepsin, which inhibit histone deacetylase enzymes responsible for removing one of these marks have been approved for use in humans. This review focuses on the progress in the development of the second generation of epigenetic modifiers able to modulate histone marks, and restore normal gene transcription.