Recent evidence highlights the important role of the brain in the control of glucose homeostasis. Hypothalamic centers sense the availability of peripheral nutrients via redundant and overlapping nutrient-induced peripheral signals such as leptin and insulin and via direct metabolic signaling. Responding to nutrient availability, these hypothalamic regions in turn exert a negative feedback not only on food intake but also on endogenous glucose production. Disruptions in the mechanisms of central nervous system nutrient sensing alter these homeostatic responses and contribute to the pathophysiology of obesity and type 2 diabetes. In this review, we discuss the neural and molecular pathways so far identified as possible targets for therapeutic intervention.