Diabetic cardiomyopathy has become a major contributor to the increased mortality of diabetic patients. Although the development and progression of diabetic cardiomyopathy are considered to be associated with diabetes-derived oxidative stress, the precise mechanisms for and effectively preventive approaches to diabetic cardiomyopathy remain to be explored. Recent studies showed that reactive oxygen or nitrogen species (ROS/RNS) not only play a critical role in the initiation of diabetic cardiomyopathy, but also play an important role in physiological signaling. Therefore, this review will first discuss the dual roles of ROS/RNS in the physiological signaling and pathogenic remodeling leading to cardiomyopathy under diabetic conditions. The significant prevention of diabetic cardiomyopathy by metallothionein (MT) as a potent and nonspecific antioxidant will be also summarized. It is clearly revealed that although dual roles of peroxynitrite-nitrated proteins have been indicated under both physiological and pathogenic conditions, suppression of nitrative damage by MT in the diabetic heart is the major mechanism responsible for its prevention of diabetic cardiomyopathy. Finally the potential for clinical enhancement of the cardiac MT expression to prevent or delay the occurrence of cardiomyopathy in diabetic patients will also be addressed.