The neuroendocrine brain or hypothalamus has emerged as one of the most highly sexually dimorphic brain regions in mammals, and specifically in rodents. It is not surprising that hypothalamic nuclei play a pivotal role in controlling sex-dependent physiology. This brain region functions as a chief executive officer or master regulator of homeostatic physiological systems to integrate both external and internal signals. In this review, we describe sex differences in energy homeostasis that arise in one area of the hypothalamus, the ventrolateral subregion of the ventromedial hypothalamus (VMHvl) with a focus on how male and female neurons function in metabolic and behavioral aspects. Because other chapters within this book provide details on signaling pathways in the VMH that contribute to sex differences in metabolism, our discussion will be limited to how the sexually dimorphic VMHvl develops and what key regulators are thought to control the many functional and physiological endpoints attributed to this region. In the last decade, several exciting new studies using state-of-the-art genetic and molecular tools are beginning to provide some understanding as to how specific neurons contribute to the coordinated physiological responses needed by male and females. New technology that combines intersectional spatial and genetic approaches is now allowing further refinement in how we describe, probe, and manipulate critical male and female neurocircuits involved in metabolism.