Loss of adequate coupling between metabolism and K_ATP channel closure has been identified as a key determinant for beta-cell failure in type 2 diabetes mellitus. Consequently, K_ATP channel inhibitors are well-established drugs to treat diagnosed type 2 diabetics. In addition to this therapeutic concept modulation of K_ATP channel activity is currently under investigation for its potential to delay diabetes manifestation. During diabetes development the beta-cells are exposed to increased oxidative stress mainly caused by excessive nutrient supply. Because of their low antioxidant capacity beta-cells are extremely vulnerable to oxidative stress. In rodents knockout of K_ATP channels attenuates the detrimental effects of oxidative stress on both, beta-cell function and viability, and protects in vivo against experimentally induced hyperglycemia. These observations indicate that prevention of oxidant-evoked alterations in K_ATP channel activity might be suited to preserve beta-cell function and, finally, to decelerate progression to glucose intolerance. Importantly, beta-cell protection can also be achieved pharmacologically by application of K_ATP channel inhibitors. Sulfonylureas up-regulate the activity of antioxidant enzymes thereby rendering the islet cells less susceptible to apoptotic cell death and reduced insulin secretion in response to oxidative stress. Compared to other sulfonylureas gliclazide seems to be superior because it does not interfere with cell viability per se. For humans at risk for metabolic disease increasing antioxidant capacity at an early stage via modulation of K_ATP channel-regulated pathways might be a long-term strategy to preserve beta-cell mass and function.