Creating a Learning Health System (LHS) that overcomes the artificial barriers between clinical care and research will require significant learning and change. We have developed extensive, world recognized expertise and capacity in health system transformation and have demonstrated that a network organizational model to create LHSs works at scale. Our objective is to develop and test interventions that facilitate the emergence of two pilot LHSs within our Academic Health Center (AHC). We will pursue two specific aims to: 1) engage stakeholders in co-designing and collaboratively testing interventions to facilitate emergence of LHSs that improve outcomes by integrating clinical/translational research with health care practice; and 2) develop a collaborative laboratory to further advance best practices for instantiating the networked organization by aligning and integrating functions across existing Center for Clinical and Translational Science and Training (CCTST) Cores. As a result of the proposed effort, we expect to have a replicable, tested approach to facilitating the emergence of LHSs within the AHC, as well as workforce, scientific, and informatics infrastructure to enable the CCTST to function as a learning system to pursue this work at the AHC and across the CTSA network. This is significant because it will further advance knowledge for how to accelerate the translation of research into improved outcomes and lead to better care and health for our region and the nation.