Emerging evidence indicates that the hypothalamus is a key regulator of the adaptation of the central nervous system (CNS) to the changing environment in support of survival. Subsets of hypothalamic neurons acting in conjunction with glia cells are upstream regulators of brain regions classically considered as master determinants of CNS function, such as the cortex and hippocampus. The regulatory role of the hypothalamus in cortical and hippocampal functions is mediated via classical neuronal pathways and by the regulation of peripheral tissue output in the form of hormones and nutrients. I will argue that when the relationships between these brain regions and peripheral tissues are reconsidered based on these driving principles of health and survival, it is challenging to envision that long-lasting successful strategies to combat obesity and diabetes can emerge from propagation of satiety and energy expenditure. We also argue that many hypothalamus-driven metabolic principles will have important implications for neurological and psychiatric conditions, aging and chronic diseases in general.