Obesity and type 2 diabetes mellitus represent a significant global health crisis.  These two interrelated diseases are typified by perturbed insulin signaling in the hypothalamus.  Using novel hypothalamic cell lines, we have begun to elucidate the molecular and intracellular mechanisms involved in the hypothalamic control of energy homeostasis and insulin resistance.  In this review, we present evidence of insulin and glucose signaling pathways that lead to changes in neuropeptide gene expression.  We have identified some of the molecular mechanisms involved in the control of de novo hypothalamic insulin mRNA expression.  And finally, we have defined key mechanisms involved in the etiology of cellular insulin resistance in hypothalamic neurons that may play a fundamental role in cases of high levels of insulin or saturated fatty acids, often linked to the exacerbation of obesity and diabetes.