Child and adolescent posttraumatic stress disorder (PTSD) is associated with an increased risk for a number of deleterious mental and physical health outcomes that if untreated may persist throughout the life course. Efficacious interventions applied soon after trauma exposure have the potential to reduce or prevent the development of PTSD symptoms and their associated impact on behavior and physical health. We review extant research related to treatment-modifiable peritraumatic predictors of pediatric PTSD, which have informed an emerging field of pharmacologic secondary prevention (i.e., occurring shortly following trauma exposure) of PTSD. Challenges and opportunities for early posttrauma PTSD prevention are described. Finally, we offer new models for biologically informed integration of pharmacologic and psychosocial secondary prevention intervention strategies for children and adolescents.