The tools and knowledge base for personalized medicine practices are being developed as a major transformation is underway in our health care system. Although the foundation supporting the scientific and technological applications that enable individualized approaches in health care continues to be framed, an uncertain health care delivery landscape lies ahead, driven by economic, quality-of-care, and other policy considerations. There are commonalities in the needs and the opportunities for personalized medicine and health care system change, and these 2 facets can mutually inform one another. Here, we examine this interface in the dimensions of innovation and costs, health information technology, evidence development and comparative effectiveness, clinical data standards, consumer tools, and patient safety and public health. Indeed, personalized medicine must offer solutions for broader health priorities if it is to achieve its potential impact.