Obesity has become a worldwide public health problem which affects millions of people. Substantial progress has been made in elucidating the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Twin, adoption and family studies have shown that genetic factors play a significant role in the pathogenesis of obesity. Human monogenic obesity is rare in large populations. The most common form of obesity is considered to be a polygenic disorder. New treatments are currently required for this common metabolic disease and type 2 diabetes. The identification of physiological and biochemical factors that underlie the metabolic disturbances observed in obesity is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the pathogenesis of such a disease is critical to this process. However, identification of genes that contribute to the risk of developing the disease represents a significant challenge since obesity is a complex disease with many genetic and environmental causes. A number of diverse approaches have been used to discover and validate potential new genes for obesity. To date, DNA-based approaches using candidate genes and genome-wide linkage analysis have not had a great success in identifying genomic regions or genes involved in the development of these diseases. Recent advances in the ability to evaluate linkage analysis data from large family pedigrees (using variance components-based linkage analysis) show great promise in robustly identifying genomic regions associated with the development of obesity. Studying rare mutations in humans and animal models has provided fundamental insight into a complex physiological process, and has complemented population-based studies that seek to reveal primary causes. Remarkable progress has been made in both fronts and the pace of advance is likely to accelerate as functional genomics and the human genome project expand and mature. Approaches based on Mendelian and quantitative genetics may well converge, and ultimately lead to more rational and selective therapies.