Many treatments for acute ischemic stroke are vessel and blood based, but brain-based therapies also hold great promise. Acute neuroprotective therapies block the molecular elaboration of injury in hypoxic environments. Prehospital trials of magnesium sulfate are demonstrating the feasibility of delivering potentially brain-protective agents in the first minutes after stroke onset. Subacute neurorestoration therapies enhance neuroplasticity and brain reorganization after stroke. The greatest clinical experience with agents that can potentiate brain repair has been gained with choline precursors. Therapies that target the brain in patients with stroke will increasingly complement and enhance traditional vasotherapeutics.