Vision is routinely ranked as one of the most important features of healthy aging, often ranked above other senses, or even memory. Recent decades have seen major advances in treatment of important ocular diseases including glaucoma, presbyopia, and age-related macular degeneration. However, a significant need remains for treatment of diseases affecting the posterior cornea, particularly the corneal endothelium. The mainstay of corneal endothelial disease intervention remains corneal transplant, an invasive procedure that relies on donor tissue availability, and which requires patients to suffer through years of progressive visual impairment to reach end-stage corneal disease before eligibility. Developments in advanced biomaterials and stem cell approaches are promising, and appear likely to provide improved outcomes with less reliance on transplantation for end-stage corneal disease patients. Yet, no pharmacologic therapies have emerged to offer the potential to arrest, reverse, or prevent corneal endothelial cell disease in earlier stage patients. This review summarizes recent developments in the role of oxidative stress in both acute and chronic corneal endothelial cell (CEC) dysfunction, and highlights the potential for activation of NRF2 as a disease-modifying therapeutic pathway in corneal endothelial disease.