The loss of light-sensing photoreceptors represents the main cause for visual impairment and blindness in industrialized societies with no curative therapy established clinically. Transplantation of donor photoreceptors is discussed as a general treatment option aiming to replace degenerated photoreceptors. Indeed, recent technology progress allows the generation of human photoreceptors within pluripotent stem cell-derived retinal organoids in sufficient amounts in vitro. First pre-clinical studies in vivo provide evidence for some functional improvements after transplantation into animal models of retinal degeneration. However, the cellular and molecular requirements and mechanisms that allow successful structural and functional integration including connectivity with cells of the recipient retina are currently unknown. Additionally, while complete photoreceptor loss is the final stage of retinal degenerative diseases, the underlying causes and the dynamics of disease progression are highly diverse resulting in very heterogenous recipient environments. Therefore, based on our established pre-clinical transplantation pipeline using human induced pluripotent stem cell-derived photoreceptors, integration kinetics of transplants, transcriptome and proteome changes of endogenous retinal cells, as well as different degeneration stages of recipient mice will be assessed to identify cellular and molecular needs for successful photoreceptor replacement. Acquired knowledge will be of utmost importance for defining prerequisites as well as potential targets for modification of the recipient environment to optimize graft integration, organization and maturation with the ultimate goal to significantly improve visual perception within different retinal pathologies.