A better understanding of the integrative role of the central nervous system (CNS) in energy homeostasis and the regulation of hunger and satiety in humans is of crucial importance for classifying patients beyond “simple obesity" and eventually designing novel individualized drug and behavioural therapies. Energy homeostasis and regulation of body weight is regulated by homeostatic processes and hedonic experience and is organised in a complex neuroendocrine network of systemic mediators and interrelated neuronal systems. Peripheral signals regulating food-intake involve a wide range of gut hormones (such as Ghrelin, GLP-1, PYY, insulin, CCK) as well as autonomous neuronal input and adipocyte endocrine signals. The hypothalamic POMC/AgRP pathway is possibly the best-deciphered system for central regulation of food-intake. However, it is increasingly appreciated that the regulation of energy homeostasis is far more complex and that changes in energy expenditure e.g. by alteration of locomotor activity or uncoupling processes are equally important (Saper & Elmquist, Neuron 2002). Besides these mechanistic considerations, energy homeostasis is increasingly viewed as a multistage process coordinated within networks of brain structures (Kringelbach, Nature Rev 2005) with the rewarding nature of food intake being a strong stimulus. Neuroimaging via PET or fMRI is emerging as an important tool for the neuroanatomical dissection of CNS regions relevant for energy homeostasis in humans but there is no widely accepted design for neuroimaging experiments in the hunger/satiety field. In a landmark study, increased regional CBF in specific brain regions e.g. the hypothalamus, the anterior cingulate cortex, the insula, the parahippocampal gyrus and the hippocampus was found in hungry lean volunteers (Tataranni et al. PNAS 1999). In contrast, satiation was associated with increased regional CBF e.g. in the ventromedial prefrontal cortex, the dorsolateral prefrontal cortex and the inferior parietal lobe. Further PET and fMRI studies have expanded on this and have also provided first evidence that CNS activity in relation to eating behaviour may differ in lean and obese individuals (Tataranni, P. A. & Delparigi, Obes.Rev. 4, 229; 2003). While it will remain difficult to allocate a specific neuroimaging signal to „hunger“, together with evidence from animal studies neuroanatomical regions and circuitries are slowly emerging. One model (suggested by S. Amiel, K. Anthony, L. Reed et al. Diabetes 2006) to reconcile many of the available data related to hunger and satiation includes regions/circuits for 1) reward seeking behaviour, 2) fear and vigilance, 3) hedonic perception and 4) visceral control of appetite. Conceivably, hormones (Ghrelin, PYY, leptin, GLP-1), substrates (glucose, fatty acids, amino acids) and neural factors as well as pharmacological interventions modulate reward value and subjective hedonic experience with different impact on food perception and intake. In addition, it is possible that these networks are affected by learning and behavioural changes. Moreover, any of these systems may not only affect energy intake but also energy expenditure.