The ability to "see" both incoming and circulating nutrients plays an essential role in the maintenance of energy homeostasis. As such, nutrient-sensing mechanisms in both the gastrointestinal tract and the brain have been implicated in the regulation of energy intake and glucose homeostasis. The intestinal wall is able to differentiate individual nutrients through sensory machinery expressed in the mucosa and provide feedback signals, via local gut peptide action, to maintain energy balance. Furthermore, both the hypothalamus and hindbrain detect circulating nutrients and respond by controlling energy intake and glucose levels. Conversely, nutrient sensing in the intestine plays a role in stimulating food intake and preferences. In this review, we highlight the emerging evidence for the regulation of energy balance through nutrient-sensing mechanisms in the intestine and the brain, and how disruption of these pathways could result in the development of obesity and type 2 diabetes.