Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed.