Mothercraft's Breaking the Cycle is an early intervention program for substance-exposed children with neurodevelopmental vulnerabilities. Within three substance-exposed sibling groups (N = 8; 0-6 years), we 1) described longitudinal neurodevelopmental trajectories, 2) explored the balance of cross-domain cumulative risk and protection on neurodevelopment, and 3) generated hypotheses on how cumulative risk, protection, and early intervention impact neurodevelopment. Neurodevelopment is potentially shaped by the balance of risk and protection. Postnatal risk (birth/postnatal, child, parent-child interaction) and relational protection (family, parent-child interaction) appear to have the most salient impact on neurodevelopment. Early intervention is thought to be important as soon as possible and before age 3 years.