In response to a growing chronic disease burden and ageing population, Singapore implemented Regional Health Systems (RHS) in 2008. In January 2017, the MOH announced that the six RHS clusters would be reorganised into three in 2018. This qualitative study sought to identify the health system challenges, opportunities, and ways forward for the implementation of the RHS. We conducted semi-structured interviews with 35 key informants from RHS clusters, government, academia, and private and voluntary sectors. Integration, innovation, and people-centeredness were identified as the key principles of the RHS. The RHS was described as an opportunity to holistically care for a person across the care continuum, address social determinants of health, develop new models of care, and work with social and community partners. Challenges to RHS implementation included difficulties aligning the goals, values, and priorities of multiple actors, the need for better integration across clusters, differing care capabilities and capacities across partners, healthcare financing structures that may not reflect RHS goals, scalability and evaluation of pilot programmes, and disease-centricity, provider-centricity, and medicalisation in health and healthcare. Suggested ways forward included building relationships between actors to facilitate integration; exploring innovative new models of care; clear long-term/scale-up plans for successful pilots; healthcare financing reforms to meet changing patient and population needs; and developing evaluation systems reflective of RHS principles and priorities.