Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways. We found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese (n=46) versus lean (n=26) populations. Computational analysis further predicted a significantly greater fraction of deleterious variants within the obese cohort. Consistent with the complex inheritance of body weight, we did not observe obvious familial segregation in the majority of the 28 available kindreds. Taken together, these data suggest that multiple rare alleles with variable penetrance contribute to obesity in the population and provide a deep medical sequencing based approach to detect them.