Cardiomyocytes mainly depend on energy produced from the oxidation of fatty acids and mitochondrial oxidative phosphorylation. Shortage of energy or excessive fat accumulation can lead to cardiac disorders. High saturated fat intake and a sedentary life style have a major influence in the development of cardiovascular disease (CVD). Peroxisome proliferator-activated receptors (PPARs), one of the nuclear receptor super family members, play critical role in the metabolism of lipids by regulating their oxidation and storage. Furthermore, they are involved in glucose homeostasis as well. PPARs, mainlyalpha(α) andbeta/delta(β/δ), have a significant effect on the lipid metabolism and anti-inflammation in endothelial cells (ECs), vascular smooth muscle cells, and also in cardiomyocytes. Pro-inflammatory cytokines, mainly tumour necrosis factor-α, released at the site of inflammation in the sub-ECs of coronary arteries can inactivate the PPARs which can eventually lead to decreased energy production in the myocardium. Various synthetic ligands of PPAR-αandβ/δhave many favourable effects in modulating the vascular diseases and heart failure. Despite the adverse effects from therapy using PPAR- gammaligands, several laboratories are now focused on synthesizing partial activators which may combine their beneficial effects with lowering of undesirable side effects. This review discusses the role of isoforms of PPAR in the cardiomyocytes energy balance and CVD. The knowledge will help in the synthesis of ligands for their partial activation in order to render energy balance and protection from CVD.