In this review, we discuss an immunological-driven sign termed the Completed Self, which is related to a holistic determination of health vs. disease. This sign (human plus commensal microbiota) forms the human superorganism. The worldwide emergence of an epidemic of chronic diseases has caused increased healthcare costs, increased premature mortality and reduced quality of life for a majority of the world’s population. In addition, it has raised questions concerning the interactions between humans and their environment and potential imbalances. Misregulated inflammation, a host defense-homeostasis disorder, appears to be a key biomarker connecting a majority of chronic diseases. We consider the apparent contributors to this disorder that promote a web of interlinked comorbid conditions. Three key events are suggested to play a role: (1) altered epigenetic programming (AEP) that may span multiple generations, (2) developmental immunotoxicity (DIT), and (3) failure to adequately incorporate commensal microbes as a newborn (i.e., the incomplete self). We discuss how these three events can combine to determine whether the human superorganism is able to adequately and completely form during early childhood. We also discuss how corruption of this event can affect the risk of later-life diseases.