Obesity is a health problem of epidemic proportions in the industrialized world. The cloning and characterization of the genes for the five naturally occurring monogenic obesity syndromes in the mouse have led to major breakthroughs in understanding the physiology of energy balance and the contribution of genetics to obesity in the human population. However, the regulation of energy balance is an extremely complex process, and it is quickly becoming clear that hundreds of genes are involved. In this article, we review the naturally occurring monogenic and polygenic obese mouse strains, as well as the large number of transgenic and knockout mouse models currently available for the study of obesity and energy balance.