Elevated blood glucose alone cannot explain the development and progression of diabetic neuropathy (DN) and the lowering of blood glucose is insufficient in preventing and/or reversing neuropathy in patients with type 2 diabetes. Dicarbonyls, such as methylglyoxal (MG), are endogenous by-products of glycolysis, which are elevated in diabetic patients. Reactive metabolite such as MG can modify DNA as well as extra- and intracellular proteins, leading to the formation of advanced glycation endproducts (AGEs). MG can contribute to the development of DN via post-translational modification of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. Increased formation of AGEs leads to increased cellular stress, dysfunction and ultimately cell death. The interaction of AGE-modified proteins through cell surface receptors, such as RAGE, can lead to increased cellular activation and sustained inflammatory responses. An inflammatory immune response is associated with later, degenerative, stages of DN. The direct and indirect effects of dicarbonyls on nerves provides a unifying mechanism for the development and progression of DN. Preventing the accumulation of MG during diabetes and/or inhibiting of RAGE signalling may therefore provide new, more effective, therapeutic approaches for the treatment of DN.