Leptin has emerged as a major regulator of adiposity. Leptin is released into the blood from fatcells and circulates to the brain where it crosses the bloodbrain barrier (BBB) to act at receptors within the central nervous system to affect appetite, thermogenesis, and a number of other actions. In humansand in many rodent models, resistance to leptin appears to be a chief cause of obesity. Determining the cause of leptin resistance is fundamental to developing strategies for the use of leptin in obesity. Theliterature characterizing the transport of leptin across the BBB is reviewed. This literature stronglysuggests that the cause of leptin resistance is due a decreased transport of leptin across the BBB in obese humans and rodents. The main cause of this resistance appears to be an impairment in the activity of the transporter rather than just simply saturation at higher doses. Strategies to overcome impaired BBB transport are reviewed, including the use of allosteric regulators and the delivery of material by the intrathecal route.