Introduction Population Health Management initiatives are increasingly introduced, aiming to develop towards sustainable health and wellbeing systems. Yet, little is known about which strategies to implement during this development. This study provides insights into which strategies are used, why, and when, based on the experiences of nine Dutch Population Health Management initiatives. Methods The realist evaluation approach was used to gain an understanding of the relationships between context, mechanisms and outcomes when Population Health Management strategies were implemented. Data were retrieved from three interview rounds (n = 207) in 2014, 2016 and 2017. Data was clustered into guiding principles, underpinned with strategy-context-mechanism-outcome configurations. Results The Dutch initiatives experienced different developments, varying between immediate large-scale collaborations with eventual relapse, and incremental growth towards cross-sector collaboration. Eight guiding principles for development towards health and wellbeing systems were identified, focusing on: 1. Shared commitment for a Population Health Management-vision; 2. Mutual understanding and trust; 3. Accountability; 4. Aligning politics and policy; 5. Financial incentives; 6. A learning cycle based on a data-infrastructure; 7. Community input and involvement; and 8. Stakeholder representation and leadership. Conclusion Development towards a sustainable health and wellbeing system is complex and time-consuming. Its success not only depends on the implementation of all eight guiding principles, but is also influenced by applying the right strategies at the right moment in the development.