Important advances have been made in reperfusion therapies for acute ischemic stroke. However, a majority of patients are either ineligible for or do not respond to treatments and continue to have considerable functional deficits. Stroke results in a pathological disruption of the neurovascular unit (NVU) that involves blood-brain barrier leakage, glial activation, neuronal damage and chronic inflammation, all of which create a microenvironment that hinders recovery. Therefore, finding ways to promote central nervous system recovery remains the holy grail of stroke research. Here we propose a conceptual framework to synthesize recent progress in the field, which is currently dispersed and disconnected in the literature. We suggest that stroke recovery requires an integrated reprogramming process throughout the brain that occurs at multiple levels, including changes in gene expression, endogenous cellular transdifferentiation within the NVU, and reorganization of larger-scale neural and social networks.