As the twenty-first century unfolds, medicine is facing several significant challenges that threaten to cripple its advancement and practice. One of the responses to these challenges is the emergence of systems medicine, and one of the more pertinent challenges is identifying and clarifying systems medicine’s conceptual and theoretical foundations. This book represents a sustained effort to examine this challenge and to map the terrain by which to engage it and to pursue possible solutions. This conceptual and theoretical challenge in particular needs to be addressed to ensure the future success of systems medicine. To that end the book explores the conceptual and theoretical foundations of systems medicine, including the major concepts of organicism, emergence, and robustness, and contrasts these concepts with those of biomedicine, including mechanism, resultant, and homeostasis. Moreover, this challenge is critical because its resolution provides the intellectual scaffolding necessary for structuring the concepts and theories required to understand and explain more adequately or completely biological, physiological, and pathological mechanisms and processes. Importantly, with a robust conceptual and theoretical scaffolding, systems medicine must be implemented interdisciplinarily, not only within the medical community, but also within the social and political communities, which the COVID-19 pandemic made so painfully obvious.