Leptin is a 16,000-Da protein which is secreted by fat but acts within the brain to regulate adiposity. Our Peptides Classic addressed the mystery of how such a large molecule could negotiate the blood-brain barrier (BBB), a structure which normally excludes proteins from the brain. We found that leptin was transported across the BBB by a saturable transport system. This finding was important to understanding how satiety-related peptides and proteins worked, but it was also important to the concept that the BBB is a regulatory interface important in brain-body communication. Obesity in humans and many animals is associated with a leptin resistant state rather than a leptin deficiency. Subsequent work has shown that a defect in the BBB transport of leptin is key in producing and reinforcing this state of resistance. Leptin is pluripotent and the concept of it being primarily an adipostat is being discarded for more encompassing views. Consideration of the BBB data would favor the view that ancestral levels of leptin were much lower than those currently considered normal and are consistent with leptin acting as a metabolic switch, informing the brain when fat reserves are adequate to direct energy expenditures towards activities other than seeking calories.