Obesity and diabetes are two major public health problems in Australia and worldwide. Obesity develops when energy intake exceeds energy expenditure over time while diabetes is characterized by elevated blood glucose levels due to insufficient insulin secretion and/or insulin action. Many factors have been implicated in the control of energy/glucose homeostasis, among which, neuropeptide Y (NPY) and its cognate receptors, expressed centrally and peripherally, are critical regulators in these two processes. Elevation of NPY level in the hypothalamus promotes food intake as well as reduces energy expenditure via the suppression of brown adipose tissue activity, and this action is mediated by the sympathetic nervous system. In addition to the brain, NPY and its major Y1 receptor (Y1R) are extensively expressed in peripheral tissues, including pancreatic islet beta cells and adipose tissue, two tissues that are important in the pathophysiology of diabetes and obesity. Deletion of Y1R specifically in pancreatic beta cells leads to increased insulin release and improves islet transplant efficiency in type 1 diabetes mouse models. Moreover, antagonism of NPY-Y1R signaling in adipose tissue increases energy expenditure through the activation of brown adipose tissue and white adipose tissue browning, leading to reduced adiposity and improvement in glucose tolerance under high fat and high calorie feeding. Together, our findings highlight the key roles of the NPY family in the control of energy/glucose metabolism. In particular, targeting peripheral NPY-Y1R signaling can be an attractive strategy for safer and more effective obesity and diabetes interventions.