BACKGROUND: For the design of optogenetic treatment approaches for degenerative retinal disorders two factors are of key relevance: firstly, the treatment targets a diseased retina where morphology and function may already be severely altered. These alterations are referred to as remodeling. The second factor is the complex signal processing in the retina, which may be altered by this remodeling or short-circuited by optogenetic therapy. RESEARCH QUESTION: This article presents the current state of knowledge on disease-related morphological and functional remodeling processes in the retina and discusses the challenges for optogenetic treatment approaches. MATERIAL AND METHODS: The article presents a narrative review. RESULTS: Although hereditary diseases, such as retinitis pigmentosa primarily affect the outer retina, the structural and functional remodeling processes eventually affect all retinal layers. The current understanding of this process is largely based on animal studies. State-of-the-art, high-resolution imaging methods could help to gain a better understanding of remodeling in human patients and could enable identification of the optimal target cell population for optogenetic treatment approaches in patients with advanced retinal degeneration, depending on the stage of the disease. CONCLUSION: Remodeling processes and retinal signal processing must be taken into account when designing optogenetic treatment approaches. In the long term the goal must be to develop targeted approaches for both ganglion cells and bipolar cells in order to make optimal use of the remaining functions depending on the stage of the disease.