Much of the permanent damage that occurs in response to nervous system damage (trauma, infection, ischemia, etc.) is mediated by endogenous secondary processes that can contribute to cell death and tissue damage (excitotoxicity, oxidative damage and inflammation). For humans to evolve mechanisms to minimize secondary pathophysiological events following CNS injuries, selection must occur for individuals who survive such insults. Two major factors limit the selection for beneficial responses to CNS insults: for many CNS disease states the principal risk factor is advanced, post-reproductive age and virtually all severe CNS traumas are fatal in the absence of modern medical intervention. An alternative hypothesis for the persistence of apparently maladaptive responses to CNS damage is that the secondary exacerbation of damage is the result of unavoidable evolutionary constraints. That is, the nervous system could not function under normal conditions if the mechanisms that caused secondary damage (e.g., excitotoxicity) in response to injury were decreased or eliminated. However, some vertebrate species normally inhabit environments (e.g., hypoxia in underground burrows) that could potentially damage their nervous systems. Yet, neuroprotective mechanisms have evolved in these animals indicating that natural selection can occur for traits that protect animals from nervous system damage. Many of the secondary processes and regeneration-inhibitory factors that exacerbate injuries likely persist because they have been adaptive over evolutionary time in the healthy nervous system. Therefore, it remains important that researchers consider the role of the processes in the healthy or developing nervous system to understand how they become dysregulated following injury.