The health burden of an increasing proportion of the population being obese lies not in the elevated body weight per se but in the ensuing metabolic dysfunction, dyslipidemia and cardiovascular disease. Elevation of peripheral signaling molecules such as leptin, insulin, ghrelin not only influence appetite and metabolic function but have a major influence on the cardiovascular system via activation of the sympathetic nervous system. Obesity-induced hypertension in humans and many experimental models has now been shown to be predominately neurogenic. Recent studies using selective leptin and insulin antagonists in animal studies have now provided very convincing evidence that amplification of leptin's sympatho-excitatory action to the kidney appears to be the major mechanism. This phenomenon, which has only recently been uncovered, is slow to develop and to reverse with changing plasma leptin levels, suggesting a slow “neural adaptive” process within hypothalamic signaling. Furthermore, amplification may lie downstream from primary pro-opiomelanocortin and neuropeptide Y neurons located in the arcuate nucleus and be independent of leptin resistance and its appetite suppressing effects that have often been observed. Animal studies indicate that the neurogenic pro-hypertensive effects of leptin are evident in offspring even when they have been raised on a normal diet. If such a phenomenon also occurs in humans, the impact on future generations will be a major issue. While considerable progress has been made, particularly in recent years, further extensive studies are critical to unravel the very complex interaction between obesity, hypertension and metabolic disease.