Stroke induces a highly complex web of pathophysiology that usually leads to serious long-term -disability. Molecules from the damage-associated molecular pattern (DAMP) family immediately increase after stroke. DAMPs are known to cause massive inflammation and brain damage. Thus, they may be targets for neuroprotection. However, emerging data now suggest that DAMPs may not always be detrimental. The high-mobility group box1 (HMGB1) protein is discussed as an example of this idea. During the acute phase after stroke, HMGB1 amplifies neuroinflammation. But during the brain remodeling phase of stroke recovery, HMGB1 can mediate beneficial plasticity and enhance stem and progenitor cell recruitment, proliferation, and differentiation within damaged brain. These emerging findings support the hypothesis that HMGB1 might be an important molecule for regulating stem and progenitor cell therapies in stroke patients.