The endocannabinoid (EC) signaling (ECS) system involves the activation of receptors targeted by endogenously produced ligands called endocannabinoids that trigger specific physiologic events in various organs and tissues throughout the body. ECs are lipid mediators that bind to specific receptors and elicit cell signaling. The focus of this review is to discuss the responses that direct pathways of systemic energy metabolism. Recent findings have indicated that an imbalance of the ECS contributes to visceral fat accumulation and disrupts energy homeostasis, which are characteristics of the metabolic syndrome. Constant activation of ECS has been linked to metabolic processes that are associated with the hypothalamus and peripheral tissues of obese patients. In contrast, inhibition of ECS results in weight loss in animal and human subjects. Despite these findings, the mechanism involved in the dysregulation of ECS is unclear. Interestingly, the level of endogenous ligands, derived from arachidonic acid, can be directly manipulated by nutrient intervention, in that a diet rich in long-chain ω-3 polyunsaturated fatty acids will decrease the production of ligands to modulate the activation of target receptors. In contrast, a diet that is high in ω-6 polyunsaturated fatty acids will cause an increase in ECS activation and stimulate tissue specific activities that decrease insulin sensitivity in muscle and promote fat accumulation in the adipose tissue. The purpose of this review is to explain the components of ECS, its role in adipose and muscle energy metabolism, and how nutritional approaches with dietary ω-3 polyunsaturated fatty acids may reverse the dysregulation of this system to improve insulin sensitivity and control body fat.