Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epigenome. While the use of DNA methyl transferase inhibitors and histone deacetylase inhibitors in in vitro and in vivo models have demonstrated improvements in disease-related deficits, clinical trials in humans have been less promising. We will address recent advances in our understanding of the complexity of the epigenome with its many molecular players, and discuss evidence for a compromised epigenome in the context of an ageing or diseased brain. We will also draw on examples of species differences that may exist between humans and model systems, emphasizing the need for more robust pre-clinical testing. Finally, we will discuss fundamental issues to be considered in study design when targeting the epigenome.