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Recent estimates indicate that approximately 18% of the population in the United States can be considered obese (defined as a body mass index [BMI] ≥ 30), and this rate is even higher among ethnic populations such as Mexican Americans. This figure becomes very significant given the strong evidence for obesity as a major risk factor for a variety of chronic diseases including type 2 diabetes mellitus and coronary heart disease. The search for genes involved in the expression of obesity has been one of the focal points of the San Antonio Family Heart Study (SAFHS), a large, family-based study to examine the genetics of risk for atherosclerosis in Mexican Americans. To date, our genome scanning effort has reported two quantitative trait loci (QTLs) with pronounced effects on the expression of a variety of obesity—related phenotypes (e.g., leptin levels, fat mass, and BMI) located on chromosomes 2 and 8. We are currently working to further refine these signals and to identify the genes and allelic variants involved. Here, we summarize the latest results from our ongoing efforts to identify obesity genes in the San Antonio Family Heart Study.