During the last 25 years, leptin resistance, as observed in obesity, has been thought to be primarily due to the loss of the capacity of leptin to cross the BBB, chiefly by means of its specific transporter, but considering previously published data, the molecular mechanisms implicated in leptin resistance as well as the mechanism by which the brain pulls up leptin from the systemic circulation are poorly understood. The gene discussed is LEP; the disease is obesity due to melanocortin 4 receptor deficiency.