Locked-in syndrome is a rare and devastating condition that results in tetraplegia, lower cranial nerve paralysis, and anarthria with preserved cognition, vertical gaze, and upper eyelid movements. Although acute management is much like that of any severe stroke, rehabilitation and recovery of these patients have not been previously described. Challenges relevant to this population include blood pressure management and orthostasis, timing and appropriateness of reinstating oral feeding, ventilatory support, decannulation after tracheostomy, bowel and bladder management, vestibular dysfunction, and eye care. Targeted rehabilitation of head, neck, and trunk stability to improve function, and proper fit in an appropriate wheelchair are essential to assist with mobility. Rehabilitation interventions should include a focus on distal motor control and upright tolerance training followed by balance and mobility exercises. In addition, special considerations must be given to developing early methods of communication through use of augmentative systems to call for help and express needs. These systems along with additional technology provide the basis to promote connectivity to family and friends through the use of social media and the internet. Establishment of communication, mobility, and connectivity is essential in promoting independence, autonomy, and improving quality of life. Overall, with specialized rehabilitative care and access to the proper equipment, long-term outcomes and quality of life in these patients can be favorable.