As no large prospective study has evaluated neural vulnerability factors that predict future weight gain we tested whether neural response to receipt and anticipated receipt of palatable food and monetary reward predicted weight gain over 3-year follow-up in originally healthy-weight adolescents and whether relations were moderated by the TaqIA polymorphism, which affects dopamine signaling capacity. 153 adolescent humans completed functional magnetic resonance imaging (fMRI) paradigms assessing response to these four events; body fat was assessed yearly over follow-up. Split half analyses indicated that elevated orbitofrontal cortex response to cues signaling impending milkshake receipt predicted future body fat gain (r = .32), which is a novel finding that provides support for the incentive sensitization theory of obesity. Neural response to receipt and anticipated receipt of monetary reward did not predict body fat gain, which has not been tested previously. Replicating an interaction reported previously (Stice et al., 2008a), elevated caudate response to milkshake receipt predicted future body fat gain for youth with a genetic propensity for greater dopamine signaling by virtue of possessing the TaqIA A2/A2 allele, but lower caudate response predicted body fat gain for youth with a genetic propensity for less dopamine signaling by virtue of possessing a TaqIA A1 allele, though this interaction was only marginal (pFWE = .06). Parental obesity, which correlated with TaqIA allele status (OR = 2.7), similarly moderated the predictive effects of caudate response to milkshake receipt to body fat gain, which is also a novel finding. The former interaction implies that too much or too little dopamine signaling capacity and reward region responsivity may increase risk for overeating, suggesting the possibility of qualitatively distinct reward surfeit and reward deficit pathways to obesity.