There is emerging consensus that the growing problem of chronic disease demands major health system changes, as envisioned in the Chronic Care Model (original and expanded). Yet implementation research has documented the pitfalls of trying to implement the whole model at once; it is more effective to focus on one highly important change at a time. This article responds to decision-makers' need to set priorities by comparing the strength of evidence for different interventions. It synthesizes a broad range of literature, including numerous systematic reviews and meta-analyses, into practical guidance on optimal system design for chronic disease management and prevention.