The literature on cross-sector partnerships has increasingly focused attention on broader systemic or system-level change. However, research to date has been partial and fragmented, and the very idea of systemic change remains conceptually underdeveloped. In this article, we seek to better understand what is meant by systemic change in the context of cross-sector partnerships and use this as a basis to discuss the contributions to the Thematic Symposium. We present evidence from a broad, multidisciplinary systematized review of the extant literature, develop an original definition of systemic change, and offer a framework for understanding the interactions between actors, partnerships, systemic change, and issues. We conclude with some suggestions for future research that we believe will enhance the literature in its next phase of development. © 2018, The Author(s).