Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, including the arcuate nucleus (ARC), the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus (DMH). While most studies have focused on leptin's actions in the ARC, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used BAC transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1 (SF-1), thereby inactivating a conditional Lepr allele specifically in SF-1 neurons of the VMH. These knockout (KO) mice, designated Lepr KO^VMH, exhibited obesity, particularly when challenged with high-fat diet. On a low-fat diet, Lepr KO^VMH mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Further, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KO^VMH mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define non-redundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH.