The genetics of human body fat content (obesity) are clearly complex. Genetic and physiological analysis of rodents have helped enormously in pointing to critical molecules and cells in central nervous system and "peripheral" pathways mediating the requisite fine control over the defense of body fat. Human and animal studies are consistent with inferences from evolutionary considerations that the strengths of defenses against fat loss are greater than those against gain. Many of the genes participating in these pathways have reciprocal effects on both energy intake and expenditure, though different genes may have primary roles in respective responses to weight gain or loss. Such distinctions have important consequences for both research and treatment strategies. The body mass index (BMI) is a useful gross indicator of adiposity, but more refined measurements of body composition and energy homeostasis will be required to understand the functional consequences of allelic variation in genes of interest. Phenotypes related to energy intake and expenditure-which clearly are the major determinants of net adipose tissue storage-are not salient when individuals are in energy balance (weight stable); measurements obtained during weight perturbation studies are likely to provide more revealing phenotypes for genetic analysis. The advent of high-density genome-wide scans in large numbers of human subjects for association analysis will revolutionize the study of the genetics of complex traits such as obesity by generating substantial numbers of powerful linkage signals from smaller genetic intervals. Many of the genes implicated will not have been previously related to energy homeostasis (e.g., recent experience with FTO/FTM as described below), and will have relatively small effects on the associated phenotype(s). The mouse will again prove useful in determining the relevant physiology of these new genes. New analytic tools will have to be developed to permit the necessary analysis of the gene x gene interactions that must ultimately convey aggregate genetic effects on adiposity.