The adipose tissue-derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr(985) on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity. Several unique features of the arcuate nucleus of the hypothalamus may contribute to the severity of cellular leptin resistance in this region. Other mechanisms that govern feeding behavior and food reward may also underlie the inception of obesity.