The mammalian neuroendocrine system primarily governs homeostasis by regulating hormone secretion from the pituitary. The neuroendocrine neurons are located within the preoptic area, the paraventricular nucleus, the supraoptic nucleus, and the arcuate nucleus of the hypothalamus (figure 1). While the physiological importance of these nuclei are well documented, their developmental programs are less known (figure 2). Using the transgenic knock-out approach (figure 3), we have uncovered genes involved in the development of the hypothalamus (view publications). The ultimate goal is to build a complete genetic pathway that directs the development of resident neurons in the neuroendocrine center of the brain (figure 4). One of these genes, Sim1, has been directly implicated in maintaining energy homeostasis and interestingly, heterozigosity at the Sim1 locus causes obesity in mice and humans(figure 5).