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This paper describes multiple important opportunities for applying system of system engineering (SoSE) concepts in the 21st Century healthcare enterprise. Throughout the world, populations are aging rapidly, which is creating unprecedented economic, social, political, and technical challenges that cannot be solved using past approaches. Healthcare today is terribly wasteful of labor, material, computer, and capital resources, and its high fatigue and error rates cause unacceptable human suffering daily. SoSE methodologies, including incremental modeling, simulation, verification, and validation can help create new healthcare enterprises that are not only more efficient and more humane, but are also more readily adapted to the endless evolution of science, society, and technology, and the equally endless and unpredictable emergent behaviors that all systems inevitably provoke.