GPR109A was discovered recently as the G-protein coupled receptor for niacin (nicotinic acid), a drug used widely in the treatment of hyperlipidemia. Upon its initial discovery, expression of the receptor was thought to be restricted primarily to adipocytes and immune cells (monocytes/macrophages), a pattern of localization consistent with the known actions of niacin – anti-lipolytic and anti-atherogenic. Of late however, several new reports have arisen detailing expression of the receptor in other cell and tissue types. Interestingly, with the exception of dermal Langerhans cells, the cells responsible for skin flushing, an unwanted side effect of high-dose niacin therapy, the function of the receptor in the additional cell types described is largely anti-inflammatory in nature. The receptor might also have a role in cancer; silencing of the receptor has been reported in colon and breast cancers, and forced expression of the receptor in tumor cells induces apoptosis, thereby suggesting a tumor-suppressive role for the receptor. This supports strongly not only the critical importance of GPR109A expression and activity under normal, basal conditions, but also the strength in impact that therapies capable of augmenting or optimizing its expression and activation may have in thwarting the development and progression of inflammation and cancer. Given the key causative role of inflammation in diabetic retinopathy, and the critical lack of viable strategies for intervening early in this pathology, new therapies, particularly those targeting inflammation, are sorely needed. Herein, we describe preclinical and clinical studies documenting the expression of GPR109A, the pleiotropic effects elicited in response to its activation and the underlying mechanisms to explain these actions. This information we discuss in the context of its relevance to diabetic retina, ultimately providing insight into strategy for future targeting of the receptor and development of new therapies for prevention and treatment of retinopathy in diabetes.