To the Editor: In their critical review of candidate gene-by-environment (cG×E) interaction research, published in the October 2011 issue of the Journal, Duncan and Keller (1) raise several methodological issues that cast serious doubt on many published G×E findings. While informative in many respects, their virtually exclusive methodological perspective does not address an important conceptual issue that has emerged in recent years concerning cG×E interaction: putative risk alleles often operate as plasticity alleles (2). Duncan and Keller appear to maintain the tradition of viewing all G×E inquiry from a diathesis-stress perspective, which stipulates that individuals carrying risk alleles will be more likely to develop psychopathology in the face of adversity relative to individuals without risk alleles under the same conditions. However, as it turns out, ever more cG×E findings appear consistent with an alternative—and more evolutionarily plausible—conceptual framework: differential susceptibility. According to this theory, some individuals are, for genetic reasons, more responsive to both negative and positive environmental influences (3).