State-dependent modulation of neural activity for therapeutic purposes has received increasing attention. These closed-loop paradigms on the basis of online recorded physiological markers may improve both the efficiency and therapeutic efficacy of standard neuromodulatory interventions. By introducing this concept to the field of neurorehabilitation, even functional restoration of persistent deficits following stroke may come into reach. Previous experimental findings in animal models suggest that activity-dependent stimulation of the nervous system may strengthen neuronal connectivity by augmenting Hebbian-like plasticity. Recent technological developments in the field of closed-loop neuroprosthetics provide us with powerful tools for neural modulation. Translating restorative concepts into effective clinical practice poses, however, an ongoing challenge. Exploring the technological opportunities in a meaningful way to achieve real benefits for the affected patients will necessitate a better neurophysiological understanding of the underlying mechanisms and a continuous exchange of the different disciplines contributing to this field.