A systems approach to evolutionary biology offers the promise of an improved understanding of the fundamental principles of life through the effective integration of many biologic disciplines. It is presented that any critical integrative approach to evolutionary development involves a paradigmatic shift in perspective, more than just the engagement of a large number of disciplines. Critical to this differing viewpoint is the recognition that all biological processes originate from the unicellular state and remain permanently anchored to that phase throughout evolutionary development despite their macroscopic appearances. Multicellular eukaryotic development can, therefore, be viewed as a series of connected responses to epiphenomena that proceeds from that base in continuous iterative maintenance of collective cellular homeostatic equipoise juxtaposed against an ever‐changing and challenging environment. By following this trajectory of multicellular eukaryotic evolution from within unicellular First Principles of Physiology forward, the mechanistic nature of complex physiology can be identified through a step‐wise analysis of a continuous arc of vertebrate evolution based upon serial exaptations. There is no systematic way of understanding physiology at the present time. By reducing the process of physiologic evolution to an integrated series of cellular‐molecular steps from the unicellular state to complex traits, this goal has now been accomplished.