The retinal pigment epithelium (RPE) maintains tissue homeostasis through long-term survival, with little evidence of de novo cell production. Due to continued growth of the eye and aging, cell density decreases and RPE cells generally undergo hypertrophy. Degeneration of the central RPE causes the progressive chronic disease age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the elderly population. Besides some protective strategies, no effective cure for AMD is currently available. Recent studies revealed that substantial cell heterogeneity may be a feature that exists throughout the RPE. Importantly, certain subsets of this heterogeneous RPE cell population may contain distinct properties contributing to regeneration, with an intrinsic capacity for self-renewal. We and others identified signaling pathways critical for developmental RPE growth and differentiation, specifically the Hippo and Wnt pathways. Here we propose to explore how genetic modulation of such signaling pathways can stimulate regenerative repair in the mature mammalian RPE and to identify RPE subpopulations with regenerative potential. Our studies will provide insight into potential novel regulators stimulating an intrinsic, regenerative response in the mature RPE. Identifying candidate targets for clinical therapy is a critical step forward for treatment of RPE-related diseases with currently very limited therapeutic potential, such as atrophic AMD.