The incidence of obesity is rising rapidly in a number of countries. In the UK, for example, the proportion of adult men and women classified as obese on the basis of a BMI >30 doubled in the decade between 1980 and 1991 (Prentice & Jebb, 1995). Despite the growing problems associated with the epidemic of obesity, current treatment modalities have remained stalled. This is also true of attempts to understand the aetiology of the disorder in terms of the fundamental underlying mechanisms. Much debate in the past has focused on whether the obese are hyperphagic, or have metabolic abnormalities relating to energy expenditure. This has now evolved, however, to the point where the issue is being discussed in terms of whether energy expenditure is falling (because of inactivity) faster than the documented decline in energy consumption in the population (Prentice & Jebb, 1995). New insights into the regulation of energy balance and the fundamental causes of obesity are rapidly emerging following the recent application of molecular genetics. This paper summarizes these developments, focusing particularly on the biology of the system associated with leptin, the product of the ob (obese) gene.