Central nervous system damage in mammals leads to neuronal cell death, axonal degeneration, and formation of a glial scar resulting in functional and behavioral defects. Other vertebrates, like fish and salamanders, have retained the ability to functionally regenerate after central nervous system injury. To date research from many research organisms has led to a more concise understanding of the response of local neural cells to injury. However, it has become clear that non-neural cells of the immune system play an important role in determining the tissue response to injury. In this review we briefly consider the mammalian response to injury compared to organisms with the natural ability to regenerate. We then discuss similarities and differences in how cells of the innate and adaptive immune system respond and contribute to tissue repair in various species.