Alzheimer's disease (AD) is a sporadic, chronic neurodegenerative disease, usually occurring late in life. The last decade has witnessed tremendous advances in our understanding about the genetic basis of AD, but a large amount of the variance in disease risk remains to be explained. Epigenetic mechanisms, which developmentally regulate gene expression via modifications to DNA, histone proteins, and chromatin, have been hypothesized to play a role in other complex neurobiological diseases, and studies to identify genome-wide epigenetic changes in AD are currently under way. However, the simple brute-force approach that has been successfully employed in genome-wide association studies is unlikely to be successful in epigenome-wide association studies of neurodegeneration. A more academic approach to understanding the role of epigenetic variation in AD is required, with careful consideration of study design, methodological approaches, tissue-specificity, and causal inference. In this article, we review the empirical literature supporting a role for epigenetic processes in AD, and discuss important considerations and future directions for this new and emerging field of research. © 2013 Wiley Periodicals, Inc.