Variation in body weight and composition, as well as adipose tissue function, is regulated by environmental and genetic factors, combined with a variety of interactions, including environment-by-environment, gene-by-gene, and gene-by-environment interactions. Although the recent increase in obesity can in large part be attributed to the increased availability of low-cost but energy-dense foods and an increasingly sedentary lifestyle throughout most of the developed world, the impact of these factors is more pronounced in individuals who are genetically susceptible to these environmental insults. Hence, it is likely to be the response of an individual's genetic background to a given environment that determines susceptibility to obesity. Candidate gene studies, genome-wide linkage studies, and more recently genome-wide association studies (GWASs) have been used to decipher the effect of genetics on obesity. Heritability estimates suggest that 40–70% of the variation in obesity-related phenotypes is attributable to underlying genetic variation. To date, the findings from human cohort studies (both family and case/control studies) summarized in this chapter suggest that there are likely numerous genes impacting the expression of obesity-related phenotypes, with many of these genes seeming to have modest effects. The establishment of many population-based studies that have collected genome-wide data on genetic variation has recently led to the formation of multiple consortia facilitating powerful meta-analyses in order to identify additional genetic variation influencing obesity-related traits through GWAS, as well as to replicate and further characterize previously identified genetic variants and their gene regions. These consortia may have the power to elucidate how genetic and environmental factors act and interact to produce variation in obesity-related phenotypes.