Diabetes is a well-known risk factor for the development of cardiovascular diseases. Diabetes affects cardiac tissue through several different, yet interconnected, pathways. Damage to endothelial cells from direct exposure to high blood glucose is a primary cause of deregulated heart function. Toxic by-products of non-enzymatic glycolysis, mainly methylglyoxal, have been shown to contribute to the endothelial cell damage. Methylglyoxal is a precursor for advanced glycation end-products, and, although it is detoxified by the glyoxalase system, this protection mechanism fails in diabetes. Recent work has identified methylglyoxal as a therapeutic target for the prevention of cardiovascular complications in diabetes. A better understanding of the glyoxalase system and the effects of methylglyoxal may lead to more advanced strategies for treating cardiovascular complications associated with diabetes.