Abstract: Optic nerve degeneration is a major cause of irreversible blindness worldwide with glaucoma being the most common optic neuropathy, affecting approximately 76 million people worldwide in 2020. The optic nerve comprises axons of retinal ganglion cells (RGCs), the output neurons of the inner retina. Protecting RGCs and axons from degeneration and regenerating RGC axons to preserve and recover vision in patients with progressive optic neuropathy is an unmet need. Unlike embryonic neurons, mature neurons of the mammalian central nervous system fail to regenerate their axons following injury. The age-related loss of axon regenerative capacity of RGCs over time renders vision loss from optic neuropathy irreversible. The failure of injured RGCs to regenerate axons is largely attributed to inhibitory molecules in the extrinsic environment and a change in the intrinsic molecular makeup of aging cells. Early studies have demonstrated that RGCs require specific molecular signals for the stimulation of axon growth even without inhibitory molecules in the extrinsic environment, leading successive efforts to focus on uncovering the intrinsic signaling pathways that control axon extension during RGC development. Phosphatase and tensin homolog (PTEN), suppressor of cytokine signaling 3 (SOCS3), dual leucine zipper kinase, and krüppel-like factor (KLF) family members are some of the transcription factors and proteins that have been demonstrated to govern the intrinsic signaling pathways of axon regeneration (He and Jin, 2016). Whereas the molecular signatures that contribute to the differential axon regenerative potential between young and mature RGCs remain poorly understood, increasing evidence has revealed that microRNAs play a critical role in orchestrating the expression of transcription factors for axon growth in neurons of the central nervous system. A recent study has unveiled a previously unrecognized involvement of the miR-19a/PTEN axis in regulating the developmental decline of axon regenerative capacity in RGCs, highlighting the potential of microRNA-based therapeutics to rejuvenate aged RGCs and promote optic nerve regeneration (Mak et al., 2019).