In the past, the spinal cord was considered a hard-wired network responsible for spinal reflexes and a conduit for long-range connections. This view has changed dramatically over the past few decades. It is now recognized as a plastic structure that has the potential to adapt to changing environments. While such changes occur under physiological conditions, the most dramatic alterations take place in response to pathological events. Many of the changes that occur following such pathological events are maladaptive, but some appear to help adapt to the new conditions. Although a number of studies have been devoted to elucidating the underlying mechanisms, in humans and animal models, the etiology and pathophysiology of various diseases impacting the spinal cord are still not well understood. In this review, we summarize current understanding and outstanding challenges for a number of diseases, including spinal muscular atrophy (SMA), amyotrophic laterals sclerosis (ALS), and spinal cord injury (SCI), with occasional relations to stroke. In particular, we focus on changes resulting from SCI (and stroke), and various influencing factors such as cause, site and extent of the afflicted damage.