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Abstract Background Health care administrators must establish and promote effective partnerships with community agencies to address social determinants of health, including reducing exposure of infants and young children to chronic stress. Because infants’ experiences are inextricably tied to their caregivers, an important target for mitigating “toxic” stress exposure in early childhood is through reducing parents’ experiences of chronic stress in addition to protecting children from direct experiences of harm such as physical or sexual abuse. Conducting screening to identify when children are exposed to early life adversity is a first step; connecting families to needed support services is an essential component to addressing identified challenges. This paper presents the methodology of a three-year study of health care systems innovations designed to engage and support parents of infants to prevent and mitigate children’s toxic stress exposures. Methods Key study features included: 1) multi-component study in five U.S. communities and nine pediatric health care clinics and the families they serve, 2) a developmental evaluation approach to describe how innovations are experienced over time at three levels—community systems, pediatric providers, and families, and 3) rapid cycle feedback conducted with communities, clinics and families to co-interpret data and findings. Data sources included: 1) focus groups and interviews with community stakeholders, clinic staff, and families, 2) electronic health record and Medicaid services data extracted to assess health care quality, utilization, and financial impact, and 3) clinic-recruitment of 908 parents of infants in a longitudinal survey. Results. The sample is briefly characterized based on responses to the enrollment phase of the parent survey. Conclusions We discuss the study design elements’ contribution to generating evidence needed by innovators, communities, and clinics to modify and sustain investments in these innovations to prevent or mitigate the effects of exposure to toxic stress on young children.