Does a post-lesional rewiring exist in the central nervous system (CNS)? Whereas neuroimaging and neuromodulation techniques illustrate the extensive cortical reshaping after a brain injury, the remodeling of ascending and descending neuronal pathway is more difficult to be investigated. Here, we discuss how the studies dealing with hemispherectomy (HS) can provide interesting information about the functional and anatomical reorganization which take place after an extensive unilateral lesion. Indeed, studies in humans and animal models of HS clearly illustrate that the brain is capable of a widespread rewiring between the contralesional cortices and the subcortical structures as well as the medullary segments linked to the affected side of the body.