Learning and memory are cognitive processes that are tightly regulated. A proper genome-environment interaction is a pre-requisite for cognitive function. Epigenetic processes are central regulators of genome-environment interactions. In line with this, it has been shown that the epigenetic machinery is essential for cognitive function. With a specific focus on histone acetylation, we will discuss recent research in the field of epigenetic mechanisms of learning and memory. We will also specifically address the role of histone acetylation in age-associated memory impairment and Alzheimer’s disease and ask the question why targeting the epigenome could be a suitable strategy for neuroprotection and neuroregeneration.