Modern immunology, in many ways, is based on 3 major paradigms: the clonal selection theory (Medawar, Burnet; 1953/1959), the pattern recognition theory (Janeway; 1989), and the danger/injury theory (Matzinger, Land; 1994). The last theory holds that any cell stress and tissue injury including allograft injury, via induction of damage-associated molecular patterns, induces immunity including alloimmunity leading to allograft rejection. On the other hand, the concept precludes that "non-self " per se induces immunity as proposed by the two former theories. Today, the danger/injury model has been largely accepted by immunologists, as documented by a steadily increasing number of publications. In particular, overwhelming evidence in support of the correctness of the model has come from recent studies on the gut microbiota representing a huge assemblage of "non-self. " Here, harmless noninjurious commensal microbes are protected by innate immunity-based immune tolerance whereas intestinal injury-causing pathogenic microbes are immunology attacked. The ability of the immune system to discriminate between harmless beneficial "non-self " to induce tolerance and harmful life-threatening "non-self " to induce immunity has apparently emerged during evolution: Protection of innate immunity-controlled beneficial "non-self " (eg, as reflected by microbiotas but also by the fetus of placental mammals) as well as immune defense responses to injuring/injured "non-self " (eg, as reflected by plant resistance to biotic and abiotic stress and allograft rejection in mammals) evolved under pressure across the tree of life, that is, in plants, lower and higher invertebrates as well as lower and higher vertebrates. And evolution tells us why the overall existence of protected microbiotas really makes sense: It is the formation of the "holobiont, " - a metaorganism - that is, the host plus all of its associated microorganisms that - in terms of a strong unit of selection in evolution - provides that kind of fitness to all species on earth to successfully live, survive and reproduce. In other words: "We all evolve, develop, grow, and reproduce as multigenomic ecosystems! Regarding reproduction, another impressive example of active immunologic protection of "nonself " refers to pregnancy in placental mammals that emerged about 400 millions of years ago. Similar to "non-self " microbiotas, pregnancy in placental mammals reflects an evolution-driven phenomenon on the basis of innate immunity-controlled tolerance induction to semiallogeneic non-injuring/non-injured "non-self " aiming to ensure reproduction! Altogether, the lesson learned from evolution of how to avoid allograft rejection is clear: prevent allograft injury to induce allotolerance, in other words: create a "transplant holobiont. ".