Neurons of the arcuate nucleus of the hypothalamus appear to be sites of convergence of central and peripheral signals of energy stores, and profoundly modulate activity of the melanocortin circuits, providing strong rationale for pursuing these circuits as therapeutic targets for disorders of energy homeostasis. Recent studies in our lab and those of our collaborators have shown that leptin modulates different populations of hypothalamic cells in different ways. In this report, we outline an integrated model of leptin's action in the arcuate nucleus, derived from our electrophysiological studies of brain slice preparations taken from transgenic mice bred to express a variety of fluorescent proteins in specific cell types. We also discuss the recently withdrawn obesity drug fenfluramine, which appears to act on proopiomelanocortin neurons via serotonin (2C) receptors. Finally, we review current inquiries into the ability of the hormone ghrelin to stimulate appetite by its activation of neuropeptide Y neurons and inhibition of proopiomelanocortin neurons.