The management of patients with severe brain injuries and prolonged disorders of consciousness (DOC) raises important issues particularly with respect to their therapeutic options. The lack of treatment is challenged by new clinical and neuroimaging data indicating that some patients with prolonged DOC may benefit from therapeutic interventions, even years after the injury. The majority of the studies aiming at improving patients' level of consciousness and functional recovery includes behavioural and brain imaging open-label trials and case-reports, but several randomized clinical trials (RCT) have been conducted, especially using non-invasive brain stimulation. Only a couple of RCTs focused on the effects of drugs or sensory stimulation approaches, and only two Class II studies, on amantadine and transcranial direct current stimulation, have been published. While new therapeutic approaches seem to be valuable for patients with prolonged DOC, optimized stimulation parameters, alternative drugs or rehabilitation strategies still need to be tested and validated.