Earlier ideas that sympathetic nervous system activity is low in human obesity, contributing to weight gain through absence of sympathetically mediated thermogenesis, can now be discounted. The application of sympathetic nerve recording techniques and isotope dilution methodology quantifying neurotransmitter release from sympathetic nerves has established that the sympathetic outflows to the kidneys and skeletal muscle vasculature are activated in obese humans. The cause remains unclear. The adipocyte hormone, leptin, stimulates the sympathetic nervous system in rodents, but whether this applies in humans is uncertain. Cross-sectional studies suggest a quantitative link exists between regional sympathetic nervous tone (most notably in the kidneys) and rates of leptin release, but definitive studies documenting that leptin administration activates the human sympathetic nervous system have not been done. What might be the clinical implications of these new findings? The demonstration that the suppressed sympathetic tone characterizing many experimental models of obesity does not exist in human obesity weakens the case for the use of beta3-adrenergic agonists as thermogenic agents to facilitate weight loss. Although the neurogenic character of obesity-related hypertension is now established, whether antiadrenergic antihypertensive drugs are the preferred agents for blood pressure reduction has not been adequately tested. Multiple site central venous sampling, disclosing release of leptin into the internal jugular veins, led to the demonstration that the leptin gene is also expressed in the brain, in addition to adipocytes. Brain resistance to leptin has been inferred in human obesity, given that overweight is accompanied by high plasma leptin levels. The fact that the genes for leptin and its receptors are normally expressed in the brain in human obesity, and that release of leptin from the brain is actually increased, argues against this. Brain leptin release has the potential to override the peripheral, adipocyte leptin system.