Preventive interventions that target high-risk youth, via one-size-fits-all approaches, have demonstrated modest effects in reducing rates of substance use. Recently, substance use researchers have recommended personalized intervention strategies. Central to these approaches is matching preventatives to characteristics of an individual that have been shown to predict outcomes. One compelling body of literature on person × environment interactions is that of environmental sensitivity theories, including differential susceptibility theory and vantage sensitivity. Recent experimental evidence has demonstrated that environmental sensitivity (ES) factors moderate substance abuse outcomes. We propose that ES factors may augment current personalization strategies such as matching based on risk factors/severity of problem behaviors (risk severity (RS)). Specifically, individuals most sensitive to environmental influence may be those most responsive to intervention in general and thus need only a brief-type or lower-intensity program to show gains, while those least sensitive may require more comprehensive or intensive programming for optimal responsiveness. We provide an example from ongoing research to illustrate how ES factors can be incorporated into prevention trials aimed at high-risk adolescents.