Collaborating Research Centers were funded from 2016 through 2020 as part of the S4A program to lead research initiatives that test innovative ways of integrating medical, public health, social, and community services. In addition to conducting systems alignment research, each center served as a valuable resource and support for the S4A grantees by offering mentoring on access to data resources, research design, and communication and dissemination mechanisms. These centers conducted research aimed at solving vexing problems of fragmentation, duplication, and variation that exist in the delivery and financing of services that address social determinants of health and well-being.