For more than a decade, the Centre for Development Innovation (CDI) has been running an annual three-week international course on facilitating MSPs and social learning. This course evolved from the diverse experience of CDI staff in initiating, facilitating, and participating in multi-stakeholder partnerships in many parts of the world. Over the years, the course has been refined based on insights and feedback from hundreds of course participants. Versions of the course have also been tailor-made for numerous clients across business, government, and civil society. The guide distils this wealth of experience for a wider audience. Today’s complex and interconnected world clearly needs collaboration and partnerships between interest groups spanning the boundaries of business, government, civil society, and science. But bringing about such collaboration is no simple matter. It requires deep understanding of what enables and what stops people from working together. It requires patience, time, and commitment from leaders. However, with the right mindset, and by using the practical process steps and tools offered in this guide, much can be done to unlock people’s potential to cooperate and innovate for social and environmental good. The guide integrates practical knowledge with theoretical foundations and principles. While practical facilitation methods and tools are essential, it is even more important to be able to design processes around the underlying dynamics of human systems, power relations, conflict, and teamwork. We draw on diverse schools of thought to offer facilitators and stakeholders in partnerships a set of principles and conceptual models to help inspire creative and critical processes of change.