Despite growing concern about substance misuse in pregnancy and infants born substance-exposed, few programs have been developed that address the complex needs of this vulnerable population. This article describes the process of developing Project NESST® (Newborns Exposed to Substances: Support and Therapy), from needs assessment to program services. To understand the realities and dilemmas faced by mothers of substance-exposed newborns, the authors undertook an interview study to learn about their lived experience and treatment needs. They describe the interview study, highlight select findings, and trace how lessons learned informed program design, evaluation, and training activities.