This study responds to the gap in knowledge in translating team members’ interdisciplinary knowledge to address wicked problems. We use qualitative methodology to understand the team-building process and response to the opioid epidemic in emergency care. We collected data through direct observation of nine health system science researchers and thought leaders as they performed in team-building activities and semi-structured interviews. The cultural exchange framework informed our selection and assessment of team-building activities, and the science of team science (SciTS) framework informed our understanding of promoting interdisciplinary collaborations. We identified six themes representing three areas: (1) Knowledge Building and Strategy Development (need for interdisciplinary understanding of substance abuse and mental health in the emergency department (ED); interdisciplinary approaches to fight the opioid epidemic in the ED); (2) Team Demographics and Collaboration (prescribing and collaboration; the role of interdisciplinary team composition and effectiveness in the ED); and (3) Identity and Relationship Building (role of professional identity in contributing to interdisciplinary research; building effective organizational relationships in the ED). Members’ personal and professional connections are fundamental for developing nuanced interdisciplinary strategies to respond to the opioid epidemic in the ED. We discuss implications for strategies that promote team building and improve treatment practices.