Unique pathways to adolescents' co-occurring internalizing/externalizing problems, a severe and common form of psychopathology, remain poorly delineated; this paucity of knowledge impedes the development of personalized interventions. We examined established measures of genetic risk and early childhood temperamental dimensions to clarify potentially distinct pathways to adolescents' co-occurring internalizing/externalizing problems. Participants were drawn from a longitudinal randomized controlled trial of a family-based intervention. The study employed multiple informants and methods, including observer ratings of toddlers' negative affectivity and behavioral inhibition, and primary caregiver ratings of toddlers' inhibitory control; internalizing and aggression polygenic risk scores (PRS) based on prior meta-genome-wide association studies (GWAS); and parents' and teachers' reports of adolescents' internalizing and externalizing problems. Higher levels of the aggression PRS indirectly predicted primary caregiver- and teacher-reported co-occurring problems relative to all other groups through greater early childhood negative affectivity. Lower levels of the aggression PRS and higher levels of the internalizing PRS indirectly predicted co-occurring problems relative to the externalizing "only" and low problem groups (primary caregivers only) through greater early childhood behavioral inhibition. Findings suggest two different genetic pathways to co-occurring problems that could lead to distinct prevention and intervention efforts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).