The formation of long-term memory involves a series of molecular and cellular changes, including gene transcription, protein synthesis and synaptic plasticity dynamics. Some of these changes arise during learning and are subsequently retained throughout life. ‘Epigenetic’ regulation, which involves DNA methylation and histone modifications, plays a critical role in retaining long-term changes in post-mitotic cells. Accumulating evidence suggests that the epigenetic machinery might regulate the formation and stabilization of long-term memory in two ways: a ‘gating’ role of the chromatin state to regulate activity-triggered gene expression; and a ‘stabilizing’ role of the chromatin state to maintain molecular and cellular changes induced by the memory-related event. The neuronal activation regulates the dynamics of the chromatin status under precise timing, with subsequent alterations in the gene expression profile. This review summarizes the existing literature, focusing on the involvement of epigenetic regulation in learning and memory. We propose that the identification of different epigenetic regulators and signaling pathways involved in memory-related epigenetic regulations will provide mechanistic insights into the formation of long-term memory.