Leptin has emerged as a major regulator of body adiposity. The majority of humans with obesity have a resistance to leptin. Human and rodent studies indicate that the major cause of this resistance arises from an impaired ability of leptin to cross the blood-brain barrier, with lesser roles played by receptor and post-receptor defects. Evidence from baboons living in the wild is consistent with the hypothesis that during most of evolution serum levels of leptin were much lower than those currently considered normal. Leptin may have evolved to signal to the brain when caloric reserves were adequate to engage in reproductive and other behaviors not immediately concerned with acquisition of calories. The leptin transporter is a regulated system, with the rate of transport being increased by alpha-1 adrenergic agents and decreased by starvation. Impaired regulation of the transporter or impairments in transporter production could underlie the resistance caused by transporter defects. Evolutionary pressures would not have selected against such impairments if leptin levels were lower than those typically seen in Western society. A model that could explain how leptin transporter resistance can be acquired is presented.