Vascular complications are among the most serious manifestations of diabetes. Atherosclerosis is the main cause of reduced life quality and expectancy in diabetics, whereas diabetic nephropathy and retinopathy are the most common causes of end-stage renal disease and blindness. An effective therapeutic approach to prevent vascular complications should counteract the mechanisms of injury. Among them, the toxic effects of advanced glycation (AGEs) and lipoxidation (ALEs) end-products are well-recognized contributors to these sequelae. L-carnosine (β-alanyl-L-histidine) acts as a quencher of the AGE/ALE precursors reactive carbonyl species (RCS), which are highly reactive aldehydes derived from oxidative and non-oxidative modifications of sugars and lipids. Consistently, L-carnosine was found to be effective in several disease models in which glyco/lipoxidation plays a central pathogenic role. Unfortunately, L-carnosine is rapidly inactivated by serum carnosinase in humans. Therefore, the search for carnosinase-resistant derivatives of L-carnosine represents a suitable strategy against carbonyl stress-dependent disorders, particularly diabetic vascular complications. In this review, we present and discuss available data on the efficacy of L-carnosine and its derivatives in preventing vascular complications in rodent models of diabetes and metabolic syndrome. We also discuss genetic findings providing evidence for the involvement of the carnosinase/L-carnosine system in the risk of developing diabetic nephropathy and for preferring the use of carnosinase-resistant compounds in human disease. The availability of therapeutic strategies capable to prevent both long-term glucose toxicity, resulting from insufficient glucose-lowering therapy, and lipotoxicity may help to reduce the clinical and economic burden of vascular complications of diabetes and related metabolic disorders.