This article reviews and discusses emerging evidence suggesting an evolutionarily‐conserved connection between injury‐associated exposure of cytoskeletal proteins and the induction of tolerance to infection, repair of tissue damage and restoration of homeostasis. While differences exist between vertebrates and invertebrates with respect to the receptor(s), cell types, and effector mechanisms involved, the response to exposed cytoskeletal proteins appears to be protective and to rely on a conserved signaling cassette involving Src family kinases, the nonreceptor tyrosine kinase Syk, and tyrosine (...) phosphatases. A case is made for research programs that integrate different model organisms in order to increase the understanding of this putative response to tissue damage. (shrink)