Best disease is a rare form of macular dystrophy caused by mutations in the human BEST1 gene. BEST1 protein is highly expressed in the retinal pigment epithelium (RPE). Thus the loss of high acuity vision seen with Best disease – that involves RPE degeneration within the macula – is thought to arise from BEST1 mutations disrupting RPE functions critical for maintenance of a healthy retinal micro-environment. For example, the ability of the RPE to phagocytose and degrade damaged photoreceptor outer segments is thought to involve RPE responses to light-induced variations in osmotic pressure within the subretinal space. We therefore hypothesised that analysis of RPE containing mutant BEST1 protein would reveal impaired RPE cell volume regulation, as well as impaired phagocytosis and/or processing of photoreceptor outer segments. To test these hypotheses, we investigated RPE containing the F305S BEST1 mutation responsible for Best disease in some patients. This mutant RPE demonstrated an inability to respond to osmotic challenges, and showed reduced ability to process photoreceptor outer segments. Partial rescue of these functions in the diseased RPE was observed on application of a synthetic small molecule. Further investigations are underway to define the mechanisms by which this molecule restores these key RPE functions.