Abstract: Central nervous system (CNS) axons fail to regenerate following brain or spinal cord injury (SCI), which typically leads to permanent neurological deficits. Peripheral nervous system axons, however, can regenerate following injury. Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage. To initiate repair after peripheral nerve injury, dorsal root ganglion (DRG) neurons mobilize a pro-regenerative gene expression program, which facilitates axon outgrowth. Chromatin accessibility actively regulates this genetic program by controlling how easily transcriptional machinery can bind to DNA (Palmisano et al., 2019; Cheng et al., 2023). Thus, the molecular machinery driving changes in chromatin accessibility is a critical therapeutic target to coax axon regeneration following injury or disease. Exploiting this machinery through genetic or pharmacological interventions in CNS neurons, which fail to activate or sustain the proregenerative program following injury, represents a promising strategy to enhance regeneration. In this perspective, we examine recent discoveries on how chromatin accessibility regulates axon regeneration. We start by describing recent work that focuses on how two different posttranslational modifications of histones, acetylation and methylation, influence gene expression and axon regeneration following injury. We then describe the major unaddressed questions in this field of research. Ultimately, we expect that deeper insights into this process will uncover therapeutics to elicit regeneration and repair of the CNS following injury or disease.