Obesity has become the most prevalent nutritional disorder in post-industrialised societies and it is associated with the development of severe and costly complications such as type 2 diabetes mellitus and coronary heart disease or cancer. A large proportion of the risk of obesity is determined by the genetic susceptibility of an individual, but environmental factors conducive for the disorder play an important role in its phenotypic expression. Several candidate genes emerged from studies in animal models of obesity, but human pathophysiology is likely to be more complex. Thus, most cases of human obesity probably result from subtle interactions of susceptibility genes with environmental factors favouring deposition of excess calories as fat. The recent surge of obesity may relate to past evolutionary pressure which favoured selection of mechanisms defending body-weight against caloric restriction rather than against caloric excess. Rapidly developing new techniques in quantitative genetics and growing information from functional genomics will help to understand the interaction of environmental factors with signalling networks that regulate energy metabolism. The role of previously unknown pathways in the aetiology of obesity will be uncovered. The typing of numerous genetic variants will become possible and allow individual risk assessment for obesity and/or its associated disorders. Thus, rational and individually tailored therapies may be developed to combat obesity and its associated disorders.