Intravenous tissue plasminogen activator was the first successful stroke therapy in acute ischaemic stroke, after innumerable failed attempts at neuroprotection and neurorestoration. However, intravenous tissue type plasminogen activator has been shown to be effective in recanalizing middle cerebral artery occlusions in only about one-third of cases. The natural history of untreated acute middle cerebral artery occlusion is poor, leading to long-term disability in >70% and mortality in 20%. Recanalization alone is not the name of the game. Only timely, very rapid recanalization, achieved within minutes or at most a few hours after stroke has occurred, before irreversible brain damage develops, is effective. Is intravenous tissue type plasminogen activator the best available option we have for these patients? With recently introduced stent-based thrombectomy devices, neurointerventionalists have achieved complete recanalization rates of more than 90% in middle cerebral artery and ‘T‘ occlusions, with a mean procedural recanalization time of less than one-hour and negligible complication rates. More than 80% of patients less than 80 years of age who were treated within eight-hours after stroke onset in our centre achieved a modified Rankin score of 0–2 at three-month follow-up. The site of arterial occlusion is a factor driving the choice between a standard intravenous tissue type plasminogen activator protocol and an alternative intervention such as intravenous and/or mechanical thrombolysis to achieve early recanalization. The role of intravenous tissue type plasminogen activator must be redefined in major occlusions, and the indications for endovascular therapy must also be reappraised.