A better understanding of normal and diseased brain aging and cognition will have a significant public health impact, given that the oldest-old persons older than 85 years of age represent the fastest-growing segment in the population in developed countries, with more than 30 million new cases of dementia predicted to occur worldwide each year by 2040. Dysregulation of gene expression and, more generally, genome organization and function are thought to contribute to age-related declines in cognition. Remarkably, nearly all neuronal nuclei that reside in an aged brain had permanently exited from the cell cycle during prenatal development, and DNA methylation and histone modifications and other molecular constituents of the epigenome are likely to play a critical role in the maintenance of neuronal health and function throughout the entire lifespan. Here, we provide an overview of age-related changes in the brain's chromatin structures, highlight potential epigenetic drug targets for cognitive decline and age-related neurodegenerative disease, and discuss opportunities and challenges when studying epigenetic biomarkers in aging research.