This article explores the science of how adaptive systems respond to internal and external challenges. Drawing from a literature largely from outside health care, the authors discuss the roles of self-adjusting and interactive systems to manage the interdependence between clinical practice, information management, research, education, and professional development. They describe the role unpredictability plays in these systems, and suggest modified conceptual frameworks for the future. This framework necessitates replacing traditional methods of problem solving with ones that both foster respect for autonomy and respond flexibly to emerging patterns and opportunities. This article is the first in a series of four that explored the topic.