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Organization-focused Change Networks (OCNs), defined as networks comprised of organizations collaborating to advance a common goal, have emerged as powerful levers for fostering major change. Such networks face different dynamics than networks of individual members. Based on a multi-year study of how four OCNs and two similar networks focused on change in STEM higher education develop, function, and foster transformational change, this paper presents a data-based conceptual framework integrating environmental context, life cyle stages, and critical considerations to explain the nature and functioning of OCNs as levers for systemic change. The purpose of the paper is to present this framework and its implications for network leaders interested in practice as well as researchers interested in questions emerging from the framework.