Hemispherectomy (HS) is an effective surgical procedure aimed at managing otherwise intractable epilepsy in cases of diffuse unihemispheric pathologies. Neurological recovery in subjects treated with HS is not limited to seizure reduction, rather, sensory-motor and behavioral improvement is often observed. This outcome highlights the considerable capability of the brain to react to such an extensive lesion, by functionally reorganizing and rewiring the cerebral cortex, especially early in life. In this narrative review, we summarize the animal studies as well as the human neurophysiological and neuroimaging studies dealing with the reorganizational processes that occur after HS. These topics are of particular interest in understanding mechanisms of functional recovery after brain injury. HS offers the chance to investigate contralesional hemisphere activity in controlling ipsilateral limb movements, and the role of transcallosal interactions, before and after the surgical procedure. These post-injury neuroplastic phenomena actually differ from those observed after less extensive brain damage. Therefore, they illustrate how different lesions could lead the contralesional hemisphere to play the "good" or "bad" role in functional recovery. These issues may have clinical implications and could inform rehabilitation strategies aiming to improve functional recovery following unilateral hemispheric lesions. Future studies, involving large cohorts of hemispherectomized patients, will be necessary in order to obtain a greater understanding of how cerebral reorganization can contribute to residual sensorimotor, visual and auditory functions.