Abstract: The retinal ganglion cells (RGCs) are not able to regenerate following optic nerve injury resulting in an irreversible vision loss in patients with optic neuropathies including glaucoma. Recent findings in ocular regeneration have opened promising avenues to apply stem cell-based modalities to restore vision in progressive optic neuropathies. Stem cell-based therapies can help to improve retinal regeneration by solving two major problems: (1) by preventing secondary degeneration of RGCs and preserving the remaining vision, and (2) by replacing degenerated RGCs and promoting RGC axon regeneration in the damaged area. The first approach, known as neuroprotective therapy, uses stem cells incorporated into the degenerating retina with an aim to offer a nourishing environment for damaged RGCs resulting in anatomic and functional improvement. The second approach, known as RGC replacement therapy, ultimately aims at replacing the damaged RGCs with healthy RGCs or RGC precursors (Gao et al., 2012; Fu et al., 2019) in order to restore the visual function. Both approaches are graphically represented in Figure 1. The implementation of cell replacement therapeutic approaches requires successful generation of clinically safe and functional RGCs in an environment where the transplants survive, appropriately integrate and engraft, as well as establish neurites within the hosts’ retina and direct consequent axons towards the relevant regions in the brain (Behtaj et al., 2020). In this work, we discuss the challenges that are required to be addressed prior to the implementation of stem cell-based therapies in clinical practice and, suggest potential solutions to overcome the current limitations.