ABSTRACT Inherited retinal dystrophies (IRDs) cause progressive, irreversible vision loss and most are currently untreatable. Pathogenic variants in over 300 genes are implicated in IRDs, and variants within a single gene can cause diverse retinal phenotypes, which makes therapeutic development challenging. As an alternative to genetic strategies which are disease-specific, we propose that gene agnostic approaches using small molecule drugs have the potential to treat multiple IRDs independent of their genetic etiology. Our studies on mouse models of IRDs have identified cholesterol and ceramide as common pathogenic drivers of retinal pigment epithelium (RPE) dysfunction that culminates in retinal degeneration. Accumulation of these lipids facilitates complement- induced mitochondrial injury in the RPE, infiltration of microglia into the sub-retinal space, and eventually photoreceptor loss. Here, we will evaluate therapeutic efficacy of two small molecule drugs, a clinically approved bisphosphonate that inhibits cholesterol biosynthesis and ceramide generation (Aim 1) and a pan-adiponectin receptor agonist that stimulates ceramidase activity and promotes mitochondrial biogenesis (Aim 2), in mouse models of Stargardt disease and Batten disease. We will test the hypothesis that these drugs act as “triple threats” by lowering cholesterol and ceramide and protecting RPE mitochondria, thereby preventing microglial activation and retinal degeneration. We will use cutting-edge techniques such as intravital imaging of drug distribution, super-resolution imaging of mitochondrial dynamics in the living mouse retina, lipidomics, transcriptomics, and noninvasive evaluation of retinal structure and function to establish the ability of these drugs to safeguard the RPE and retina in disease models. These drugs have documented safety profiles and reach the retina in therapeutically effective concentrations after systemic administration, circumventing the need for invasive delivery. Therefore, they hold immense promise as novel, powerful, gene-independent therapeutics for IRDs.