The central nervous system receives hormonal cues (e.g., estrogens and leptin, among others) that influence reproduction and energy homeostasis. 17β-estradiol (E2) is known to regulate gonadotropin-releasing hormone (GnRH) secretion via classical steroid signaling and rapid non-classical membrane-initiated signaling. Because GnRH neurons are void of leptin receptors, the actions of leptin on these neurons must be indirect. Although it is clear that the arcuate nucleus of the hypothalamus is the primary site of overlap between these two systems, it is still unclear which neural network(s) participate in the cross-talk of E2 and leptin, two hormones essential for reproductive function and metabolism. Herein we review the progress made in understanding the interactions between reproduction and energy homeostasis by focusing on the advances made to understand the cellular signaling of E2 and leptin on three neural networks: kisspeptin, pro-opiomelanocortin (POMC) and neuropeptide Y (NPY). Although critical in mediating the actions of E2 and leptin, considerable work still remains to uncover how these neural networks interact in vivo.