Schools of nursing located within academic health centers have embraced expanded opportunities to lead in this era of rapid change and considerable uncertainty in US health care. These schools bear a unique responsibility to work with their clinical nursing partners to advance the care of patients, improve the health of communities and populations, and help steward the nation's health care resources. This article describes how the Emory University Nell Hodgson Woodruff School of Nursing has formed and sustained academic-practice partnerships in response to these imperatives. The structures and processes that have supported the partnerships are shared, as are the keys to success in a true partnership. The authors describe the work required to achieve mutually agreed-upon goals, along with the challenges that faculty and health care leaders have faced in their journey to system partnerships.