Human crumbs1 (CRB1) is a transmembrane protein located in the inner segment of photoreceptor cells (PRCs) and the apical membrane of Müller glia; its Drosophila orthologue, Crumbs (Crb), is found in the stalk membrane within the apical PRC membrane. Several pathologies are linked to CRB1 mutations and cause a degeneration of the neural retina, which leads to visual impairments or blindness. A number of mutations map to the large extracellular domain of CRB1; but how these mutations affect the protein and lead to retinal degeneration is not understood. In this issue (p. 2147), Milena Pellikka and Ulrich Tepass test human disease-causing CRB1 mutations and create four missense mutations in the extracellular domain of Drosophila Crb. They show that both the cytoplasmic tail and the extracellular domain of Crb are essential for PRC development. Three of four mutant Crb proteins show abnormal protein levels and are misdistributed to the light-sensing organelle, the rhabdomere. Importantly, the degeneration of PRC under light stress is accelerated compared to Crb-null mutants when the mutated forms of Crb are expressed. Further, the rhabdomere photopigment rhodopsin is affected when these mutant proteins are mislocalized in rhabdomeres. These data show that mutations associated with human retinal disease control the subcellular distribution of Crb, and can lead to abnormal rhodopsin physiology and severe retinal degradation.