Loss of sensory hair cells in the inner ear results in two global health impairments: hearing loss and balance disorders. In humans and other mammals, auditory hair cells damage is permanent and causes irreversible hearing loss. By contrast, hair cells in non-mammalian vertebrates are able to regenerate, prompting studies into the epigenetic mechanisms and signaling pathways that regulate hair cell regeneration. This review paper describes the current knowledge of the roles of epigenetic modifications and various signaling pathways in hair cell regeneration, and tries to understand how modulating their activity to promote the regenerative potential of supporting cells/progenitor cells. Understanding the mechanisms in regulating hair cell regeneration of vertebrates might shed light on the potential therapeutic targets in humans.