Currently, the only therapy approved for the treatment of acute ischemic stroke is intravenous recombinant tissue-type plasminogen activator (rt-PA) initiated within 3 hours of symptom onset. This therapy is only used in a very small percentage of stroke patients even in experienced centers. There have been many other clinical trials of thrombolytic drugs beyond the 3-hour time window and neuroprotective drugs, but none of these trials have been positive. There are many potential explanations for these unsuccessful stroke trials and many valuable lessons have been learned. Using imagging technology such as diffusion/perfusion magnetic resonance imaging (MRI) and perfusion computerised tomography (CT) will likely enhance the enhances for success in future acute stroke trials when combined with appropriate trial design and patient selection. Developing new acute stroke therapies will be a difficult but necessary task to meet the large unmet need for this important and under treated disorder.