While the hormone leptin and its receptor were discovered relatively recently, a great deal is already known about the molecular details of leptin receptor (LR) signaling and physiologic regulation. While multiple alternatively spliced LR isoforms exist, only the long (LRb) form associates with the Janus kinase 2 (Jak2) tyrosine kinase to mediate intracellular signaling. LRb initiates signaling via three major mechanisms: 1) Tyr(985) of LRb recruits SH2-containing tyrosine phosphatase (SHP-2); 2) Tyr(1138) of LRb recruits signal transducer and activator of transcription 3 (STAT3); and 3) tyrosine phosphorylation sites on the receptor-associated Jak2 likely recruit numerous undefined signaling proteins. The Tyr(985) --> SHP-2 pathway is a major regulator of extracellular signal-regulated kinase (ERK) activation during leptin signaling in cultured cells, while the Tyr(1138) --> STAT3 pathway induces the feedback inhibitor, suppressor of cytokine signaling 3 (SOCS3), as well as important positive effectors of leptin action. The Jak2-dependent activation of the insulin receptor substrate (IRS) protein --> phosphatidylinositol 3-kinase (PI3'-K) pathway appears to regulate membrane potential in LRb-expressing neurons and contributes to the regulation of feeding. The Tyr(1138) --> STAT3 pathway mediates transcriptional regulation of the hypothalamic melanocortin pathway in vivo. This pathway is required for the regulation of appetite and energy expenditure by leptin. Interestingly, the Tyr(1138) --> STAT3 pathway does not strongly regulate neuropeptide Y (NPY) and thus is not required for the control of reproduction and growth. Thus, other as-yet-undefined leptin receptor signals are central to these and perhaps other aspects of leptin action.