The prevalence of obesity has grown to an alarming magnitude, affecting more than 300 million humans worldwide. Although in most instances obesity is caused by excessive caloric consumption, only recently have we begun to understand the mechanisms involved in the loss of balance between caloric intake and energy expenditure. In the hypothalamus, groups of specialized neurons provide the signals that, under physiological conditions, determine the stability of body mass. Recent studies have shown that under certain environmental and genetic conditions, this equilibrium is lost and body adiposity may increase. Here, we review the work that provided the basis for the current understanding of hypothalamic dysfunction and the genesis of obesity.