Objective: The purpose of this article is to describe the background and experience of the Academic-Community Engagement (ACE) Core of the Mid-South Transdisciplinary Collaborative Center for Health Disparities Research (Mid-South TCC) in impacting the social determinants of health through the establishment and implementation of a regional academic-community partnership. Conceptual Framework: The Mid-South TCC is informed by three strands of research: the social determinants of health, the socioecological model, and community-based participatory research (CBPR). Combined, these elements represent a science of engagement that has allowed us to use CBPR principles at a regional level to address the social determinants of health disparities. Results: The ACE Core established state coalitions in each of our founding states-Alabama, Louisiana, and Mississippi-and an Expansion Coalition in Arkansas, Tennessee, and Kentucky. The ACE Core funded and supported a diversity of 15 community engaged projects at each level of the socioecological model in our six partner states through our community coalitions. Conclusion: Through our cross-discipline, cross-regional infrastructure developed strategically over time, and led by the ACE Core, the Mid-South TCC has established an extensive infrastructure for accomplishing our overarching goal of investigating the social, economic, cultural, and environmental factors driving and sustaining health disparities in obesity and chronic illnesses, and developing and implementing interventions to ameliorate such disparities.