The aim of the study is to investigate the influence of and interaction between lifestyle behaviors (diet and physical activity (PA)) and single-nucleotide polymorphisms (SNPs) in obesity-candidate genes (ADRB2, APOB and NOS3) on general and central adiposity. Six-hundred-and-twenty-one European-American (EA) and African-American (AA) youths aged 13-19 years were classified by ethnicity (49% AA), gender (45% male), and socioeconomic status (SES). PA and dietary intake with up to seven 24-h recalls were reported for all subjects. Percent body fat (%BF) was measured by dual-energy X-ray absorptiometry, visceral adipose tissue (VAT), and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging. Reported energy intake (EI) and vigorous PA (VPA) were negative predictors of %BF and SAAT. Carriers of the NOS3 Asp298 allele had higher %BF only in the presence of an adverse environment (low SES). Compared to the most common NOS3 haplotype, homozygotes for haplotype A-non4r-Asp had 6.1% higher %BF. Significant interactions were revealed between the ADRB2 Arg16Gly SNP and VPA on VAT, SAAT and waist circumference (WC) such that Gly16 homozygotes may benefit less from increased VPA to reduce their weight. Genetic susceptibility to increased general and central adiposity is dependent on several factors, such as SES and vigorous exercise. Improved understanding of the joint effect of genes and lifestyle on adiposity will offer new insights into obesity and may provide new avenues for personalized prevention and treatment.