After ischaemic stroke onset, potentially viable (ie, penumbral) tissue might be salvageble for as long as 48 h. By increasing the therapeutic time window for treatment of stroke with intravenous alteplase from 3-4.5 h to 9 h, many more patients could be treated. Use of a combination of diffusion-weighted and perfusion-weighted MRI or perfusion CT might improve selection of patients with penumbral tissue. Several phase II trials of alteplase lend strong biological support to the use of this strategy for up to 6 h after stroke. However, the negative results of the phase III Desmoteplase In Acute ischaemic Stroke trial (DIAS-2) with desmoteplase given up to 9 h after stroke suggest that some refinements are needed. For trials of neuroprotection, the concept of freezing the penumbra (ie, preventing further deterioration of the vulnerable tissue) might be a more realistic expectation. Recent advances in penumbral imaging technology should enable a phase III alteplase trial to be done beyond 4.5 h by use of techniques to select patients with penumbral tissue.