Obesity has reached pandemic proportions. Changes in lifestyles and changes in dietary habits, as well as unification of diets, contribute to the rising prevalence of obesity and the associated metabolic syndrome. Overweight and obesity in humans emerge as contemporary risks for diabetes type-2, cardiovascular disease and cancer. There seems to be consensus that on the background of modern life styles, genes that have been selected over the millions of years of human evolution render humans prone to obesity. These same genes which support higher accumulation of energy conferred substantial benefits to our ancestors at times of famine. By harnessing the knowledge on glucose metabolism we recognized that regulation of energy storage is a key process. We believe that the brain is critically involved in the regulation of energy metabolism. Progress in knowledge on energy metabolism has contributed to the invention of pharmacological measures aiming to help humans suppress food intake and control body weight. Most of these measures have been recalled due to several side effects, such as; increased hart rates an blood pressure, withdrawal symptoms, hypertension and kidney stones. Current understanding of the mechanism of action of cannabinoid CB1 antagonists is pointing towards the brain. It is postulated that hypothalamic CB1 receptors are responsible for pharmacological effects of CB1 antagonists on fat tissue. It is our hope that, in the near future, novel drugs will demonstrate adequate efficacy in aiding and maintaining weight loss and will enable a truly effective and safe long-term therapy without serious side effects.