Alteplase is the only Food and Drug Administration-approved intravenous (IV) thrombolytic medication for acute ischemic stroke. However, multiple recent studies comparing tenecteplase and alteplase suggest that tenecteplase is at least as efficacious as alteplase with regards to neurologic improvement. When given at 0.25 milligrams per kilogram (mg/kg), tenecteplase may have less bleeding complications than alteplase as well. This narrative review evaluates the literature and addresses the practical issues with regards to the use of tenecteplase versus alteplase for acute ischemic stroke, and it recommends that physicians consider tenecteplase rather than alteplase for thrombolysis of acute ischemic stroke.