The escalating pandemic of obesity has generated demand for a new generation of novel anti-obesity agents. Over the past 8 years numerous systems within the CNS critical to the expression of appetite and energy regulation have been revealed. With increasing knowledge we seem tantalisingly close to producing an unprecedented range of anorectic agents capable of inducing sustained clinical weight loss. However, it remains essential to establish that any test compound reduces food intake by selectively acting on the endogenous appetite system (or by inducing nausea or malaise). Only drugs (agonist or antagonist) that modify the daily flux of appetite, for instance enhancing within meal satiation and strengthening post meal satiety, can be considered as appetite suppressants with clinical potential. Systems of interest include peripheral factors released episodically prior to, during and after the consumption of food, many of which have been shown to have receptors within the Central Nervous System (CNS). These include Glucagon-Like Peptide (GLP)-1, Cholecystokinin (CCK), Gastrin Releasing Peptides (GRP), Enterostatin, Amylin, Peptide YY (PYY) and most recently Ghrelin. The identification of the hormone leptin (the ob protein), a key signal linking adipose tissue status with key CNS regulatory circuits, was arguably the key event in the current revolution in appetite research. Leptin itself may be one of a much larger class of peripheral tonic signals, with receptors within the CNS, informing the brain of the bodys energy status and providing a second set of target systems. Collectively, these episodic and tonic signals appear to be integrated in key CNS circuits containing monoamine neurotransmitters (Serotonin - 5-HT, Nor-Adrenaline - NA, and Dopamine - DA) and numerous neuropeptides (Melanocortins, Neuropeptide Y - NPY, Orexins, Cocaine and Amphetamine Regulating Transcript - CART, Agouti Related Peptide - AgRP and Galanin) all of which could be selectively targeted to reduce food intake and induce weight loss. Food intake can also be adjusted by drugs such as the cannabiniods acting upon the hedonic components of eating behaviour. However, any drug targeting the aforementioned systems must produce changes in feeding behaviour such as meal patterns and food choice consistent with a selective action on appetite. Ultimately in humans, this will be expressed in changes in meal size, reduced snacking and possibly a selective reduction in the intake of calorie dense high fat foods.