Significant improvements in population health are likely to arise when the social determinants of health are addressed. This creates a challenge for health systems, as the policy levers to influence the determinants largely lie outside of their direct control. Health agencies have been attempting to develop responses that affect these policy levers with mixed success. Success often requires particular conditions or “windows of opportunity” to be present before even small systemic change can be made. The government of South Australia has developed a practical, policy-oriented response to address the determinants of health-Health in All Policies-and has been successfully working across government for the past five years, using a policy learning process to implement this approach. This article will focus on how the South Australian Health in All Policies initiative started and the conditions that enabled South Australia to establish a centralized governance structure, harness a group of cross-sector policy entrepreneurs, and conduct health lens projects across a range of policy issues. The authors will comment on the nature of these conditions and their relevance for other governments struggling to reduce the burden of chronic disease and growing health budgets by addressing the social determinants of health.