Over the past three decades, multiple mechanisms limiting central nervous system regeneration have been identified. Here, we address plasticity arising from spared systems as a particularly important and often unrecognized mechanism that potentially contributes to functional recovery in studies of ‘regeneration' after spinal cord injury. We then discuss complexities involved in translating findings from animal models to human clinical trials in spinal cord injury; current strategies might be too limited in scope to yield detectable benefits in the complex and variable arena of human injury. Our animal models are imperfect, and the very variability that we attempt to control in the course of conducting rigorous research might, ironically, limit our ability to identify the most promising therapies in the human arena. Therapeutic candidates are most likely to have a detectable effect in human trials if they elicit benefits in severe contusion and larger animal models and pass the test of independent replication.