Given that alteplase has been the only approved thrombolytic agent for acute ischemic stroke for almost two decades, there has been intense interest in more potent and safer agents over the last few years. Tenecteplase is a bioengineered mutation of alteplase with advantageous pharmacodynamics and pharmacokinetics. The superiority of tenecteplase over alteplase has been proven by in vitro and animal studies, and it was approved for use in myocardial infarction more than a decade ago. In patients with acute ischemic stroke, tenecteplase has shown promise in randomized phase II trials and the drug is currently being tested in four phase III clinical trials that will start delivering definite results in the near future: NOR-TEST (NCT01949948), TASTE (ACTRN12613000243718), TEMPO-2 (NCT02398656), and TALISMAN (NCT02180204).