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Intravenous thrombolysis with the recombinant tissue plasminogen activator alteplase is the standard of care for patients with acute ischaemic stroke presenting within 4.5 h of symptom onset. The odds of independent survival decline steeply with longer time to treatment delivery, reflecting progressive ischaemic damage to the brain. Standards accordingly emphasise optimisation of patient pathways to minimise treatment delays. Observational data and international clinical guidelines support the safety and efficacy of alteplase in many patient groups currently excluded from treatment (e.g. seizure at onset, concomitant diabetes and previous stroke) on the basis of historical clinical trial criteria. Future evolution of thrombolysis will optimise dosing, apply advanced imaging to extend treatment to groups currently excluded and investigate novel drugs, and adjunctive drug and device therapies. To date, trials of novel therapeutic approaches that have been applied at later time points have failed to demonstrate benefit, suggesting that the future gains are likely to arise from applications within current time windows.