Although reduced cortisol reactivity to stress and increased circulating testosterone level are hypothesized to be associated with higher levels of externalizing behavior, empirical findings are inconsistent. One factor that may account for the heterogeneity in these relationships is prenatal testosterone exposure. This study examined whether the second-to-fourth digit ratio (2D:4D), a putative marker of prenatal testosterone exposure, moderates the relationships of testosterone and cortisol reactivity with externalizing behavior. Left and right hand 2D:4D and self-reported externalizing behavior were measured in a sample of 353 young adolescents (M age = 11.92 years; 178 females; 79.7% African American). Saliva samples were collected before and after a stress task and later assayed for cortisol. Testosterone levels were determined from an AM saliva sample. 2D:4D interacted with cortisol reactivity to predict externalizing behavior in males, but not females. In males, low cortisol reactivity was associated with higher levels of aggression and rule-breaking behavior, but only among subjects with low 2D:4D (i.e., high prenatal testosterone). Findings suggest the importance of a multi-systems approach in which interactions between multiple hormones are taken into account. Furthermore, results demonstrate the importance of considering the organizational influence of prenatal testosterone in order to understand the activational influence of circulating hormones during adolescence.