Disorders of consciousness (DOC) following severe structural brain injuries globally affect the conscious state and the expression of goal-directed behaviors. In some subjects,neuromodulation with medications or electrical stimulation can markedly improve the impaired conscious state present in DOC. We briefly review recent studies and provide an organizing framework for considering the apparently widely disparate collection of medications and approaches that maymodulate the conscious state in subjects with DOC. We focuson neuromodulation of the anterior forebrain mesocircuit in DOC and briefly compare mechanisms supporting recoveryfrom structural brain injuries to those underlying facilitated emergence from unconsciousness produced by anesthesia. We derive some general principles for approaching the problem of restoration of consciousness after severe structural brain injuries, and suggest directions for future research.