Human society faces serious environmental and social threats as a result of systemic unsustainable actions and values. This is a time of cultural self-evaluation and profound change. This study examines how 13 social and environmental change-based organizations, through network partnerships and a robust organizational knowledge-base, are responding to these challenges. A systems perspective was used as a guide to promote a holistic understanding of the actors within the system, their perceptions of success, strategies, actions and tools used to guide them toward sustainability. The results indicate that organizations seeking to scale-up their impact toward sustainability might benefit from the following success factors: 1. Collaboration with diverse partners to contribute to more effective interventions in complex systems, 2. Integrating comprehensive definitions of sustainability with organizational vision to facilitate success, 3. The application of leverage points and transparent prioritization processes to asure congruence between organizational purpose and actions, 4. Practices of dialogue and deep listening build rewarding partnerships and, 5. Metrics that support partnerships and gauge progress toward sustainability. In conclusion network partnerships have the potential to generate widespread sustained change and can be supported by complex systems science and a Framework for Strategic Sustainable Development.