The hypothalamus has long been appreciated to be fundamental in the control and coordination of homeostatic activity. Historically, this has been viewed in terms of the extensive neuroendocrine control system resulting from processing of hypothalamic signals relayed to the pituitary. Through these actions, endocrine signals are integrated throughout the body, modulating a vast array of physiological processes. Our understanding of the responses to endocrine signals is crucial for the diagnosis and management of many pathological conditions. More recently, the control emanating from the hypothalamus over the autonomic nervous system has been increasingly recognized as a powerful additional modulator of peripheral tissues. However, the neuroendocrine and autonomic control pathways emanating from the hypothalamus are not separate processes. They appear to act as a single integrated regulatory system, far more subtle and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and autonomic influences. The neural regulation is believed to be fine and rapid, whereas the hormonal regulation is more stable and widespread. In this chapter, we will focus on the hypothalamic control of hepatic glucose and lipid metabolism.