Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the general population. Energy metabolism disturbance is one of the early abnormalities in CVDs, such as coronary heart disease, diabetic cardiomyopathy, and heart failure. To explore the role of myocardial energy homeostasis disturbance in CVDs, it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs. In this article, we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart, focused on the metabolic regulation during neonatal and ageing heart, proposed potential metabolic mechanisms for cardiac regeneration and degeneration. We provided an overview of emerging molecular network among cardiac proliferation, regeneration, and metabolic disturbance. These novel targets promise a new era for the treatment of CVDs.