At the dawn of the twentieth century, the Flexner report catalyzed a transition in medical thought toward science-based research and practice. That paradigm shift resulted in a substantial improvement in human health. However, the advances that accompanied a biomedical reductionist paradigm—an approach to health concentrated on physiological minutia, professions working in silos, and a focus on episodic treatment—which surged exponentially after Flexner's report are not adequate for the complexity of today's health challenges. In this chapter, we make the case that we need a change in mindset similar to what resulted from Flexner's report: a historical paradigm shift from biological reductionism toward a complex social systems approach to health improvement. We introduce three overlapping and emerging perspectives that provide the theory, language, tools, and methods suitable for today's challenges: systems thinking, complexity thinking, and adaptive design. We also argue that some combination of these perspectives and approaches will provide the paradigm for the next century.