Why Does Systems Medicine Matter?Systems medicine represents the engine for progress in biomedicine and healthcare in the 21st century, and thus matters as much as chemistry and molecular biology did in the last two centuries of the past millennium, when there was a growing emphasis on the study of biological systems at the molecular level, which led to highly significant advances on our understanding of their structure and common functioning principles. In the process, it became increasingly clear that microorganisms, plants, animals, and humans are much more complex systems than those studied by classical chemistry and physics. To gain a deep understanding of the mechanisms underlying their behavior in physiology and disease, the analytical reductionist approach focusing on the identification of a limited number of elements was reaching its limits. It needed to be complemented with more global and integrative approaches based on systemic principles focusing on complex networks of interactions. Thus, over the first two decades of this century and millenium, systems biology approaches have been successfully developed using the mathematical and computational conceptual frameworks and tools developed in other scientific fields. Taking advantage of major technological and engineering advances, they now make it