Taken together, research over the last decades demonstrated a dual role of A2AR signaling in brain ischemia depending on the timepoint and the leading mechanism of injury: A2AR antagonists reduce ischemic injury early after stroke by reducing excitotoxicity, whereas A2AR agonists confer protection when being administered for several days post-ischemia by attenuating secondary sterile inflammation. The gene discussed is ADORA2A; the disease is brain ischemia.