There is increasing evidence supporting the concept that adult brain has the remarkable ability to plastically reorganize itself. Brain plasticity involves distinct functional and structural components and plays a crucial role in reorganizing central nervous system's networks after central and peripheral lesions in order to partly or totally restore lost and/or compromised functions. This plastic rearrangement occurs in fact not only after a central nervous system injury but also following a peripheral lesion. Interestingly, the existence of a certain type of maladaptive plasticity was clearly recognized in the last decade, which gives reason for example to poor out- come performances or aberrant phenomena. In this review we analyze stroke and amputees studies, as illustrative conditions of central and peripheral nervous system damage, and discuss the adaptive as well maladaptive plastic brain changes following these lesions. The emerging possibility, through neuro-imaging and neurophysiological advanced techniques, to clarify some crucial issues underlying brain plasticity will give the chance to modulate these mechanisms in a highly personalized therapy. This approach may have a tremendous impact in a variety of neuropsychiatric disorders opening a new era of restorative medicine.