Obesity is a pandemic, gateway disease that has thrived in modern, sedentary, high calorie-eating societies. Left unchecked, obesity and obesity-related diseases will continue to plague future generations with heavy burdens on economies, healthcare systems, and the quality of life of billions. There is a significant need to elucidate basic physiological mechanisms and therapies that address this global health care crisis. Oleoylethanolamide (OEA) is an endocannabinoid-like lipid that induces hypophagia and reduces fat mass in rodents. For over a decade, PPAR-α has been the most widely accepted mediator of the hypophagic action of OEA via signaling to homeostatic brain centers. Recent evidence suggests that OEA may also reduce food intake via effects on dopamine and endocannabinoid signaling within hedonic brain centers. Limited study of OEA supplementation in humans has provided some encouraging insight into OEA-based weight loss therapy, but more thorough, controlled investigations are needed. As a potential link between homeostatic and hedonic regulation of food intake, OEA is a prime starting point for the development of more effective obesity therapies.