Abstract <p>Stem cell-derived RPE replacement is a potential therapeutic for advanced AMD that is characterized by macular scarring and geographic atrophy leading to severe vision loss. Although the field of stem cell-differentiated RPE transplantation has undergone significant evolution, important gaps in our knowledge remains unaddressed. Long-term RPE cell survival and integration into the neural retina post-transplantation has yet to be established. Employing advanced imaging techniques and transcriptomics to study cellular integration and immune tolerance post-transplant, will improve our understanding. In addition, a better understanding of RPE bioenergetics, in the context of cell therapy, is crucial for developing more effective therapeutics. This is especially important for stem cell therapy, typically derived from varying somatic cells of origin, with inherently distinct metabolic profiles. This review focuses on current approaches to improve the outcomes of RPE transplantation, and thereby facilitate robust development of retinal cell therapy, to address the unmet clinical needs of patients with advanced AMD.</p> Graphical Abstract <p></p>