Since the early days of genetics research, scientists have noted certain heritable phenotypic differences that are not due to differences in the nucleotide sequence of DNA. Current evidence suggests that these "epigenetic" phenomena might be controlled by a number of mechanisms, including the modification of DNA cytosine bases with methyl groups, the addition of various chemical groups to histone proteins, and the recruitment of protein factors to specific DNA sites via interactions with non-protein-coding RNAs.In this video, JoVE presents the history of important discoveries in epigenetics, such as X-chromosome inactivation (XCI), the phenomenon where an entire X-chromosome is silenced in the cells of female mammals. Key questions and methods in the field are reviewed, including techniques to identify DNA sequences associated with different epigenetic modifications. Finally, we discuss how researchers are currently using these techniques to better understand the epigenetic regulation of gene function.