Inherited retinal diseases (IRD) represent a clinically and genetically heterogeneous group of rare diseases. IRD is a major cause of early-onset blindness affecting 350,000 people in Europe. Our group has been involved in the identification of almost 30 percent of the ~260 IRD genes, including major and less prevalent genes, and in the pathogenesis of IRD. These significant advances in the genomic underpinnings of IRD have culminated in novel therapies entering the clinic. Despite this progress, there are important knowledge gaps that hamper a molecular diagnosis in half of the cases. We and others have provided proof-of-concept for an emerging role of non-coding DNA variation in unsolved IRD, affecting splicing or regulation. We demonstrated there is an unmet need for a methodological and conceptual shift from classical coding genomics to integrative omics. Here, it is our main goal to establish a framework to solve missing heritability in IRD using multi-omics and gene editing in human cellular and animal models. First, we will dissect the regulation of IRD genes in human retina to improve functional genome annotation. Second, we will revisit phenotyping and generate relevant cellular models derived from unsolved monoallelic patients with suspected recessive IRD. Third, we will establish an integrative omics framework using genomics, transcriptomics and epigenomics to accelerate diagnosis in unsolved IRD. Fourth, we will unravel novel regulatory mechanisms underlying dominant IRD in human cellular and CRISPR/Cas9-generated animal models. Finally, we will transfer research findings to the clinic through ERN-EYE and patient advocacy organizations. Our multidisciplinary approach involves (functional) genomics, transcriptomics, epigenomics, bioinformatics, statistical genomics, deep phenotyping, ophthalmology, stem cell biology, gene editing, animal modeling, and developmental biology. Our expertise combined with a strong track record and international network offer a unique opportunity to address unmet needs to accelerate diagnosis and to understand mechanisms of IRD, and to pave the way to precision medicine in IRD.