The adipose-derived hormone leptin regulates energy balance and neuroendocrine function, and resistance to its appetite-suppressing effects might underlie common forms of obesity. Understanding the intracellular signaling pathways and hypothalamic neural circuitry by which leptin controls satiety and body weight is central to our understanding of leptin resistance and the identification of potential therapeutic targets. Here, we review the mechanisms by which leptin activates intracellular signaling and the roles of two specific leptin-activated signals [phosphatidylinositol 3-kinase and signal transducer and activator of transcription-3 (STAT3)] in the regulation of body weight and neuroendocrine function. The pathway by which leptin activates STAT3 is particularly intriguing because it is crucial for the regulation of feeding but dispensable for the control of reproductive and growth axes.