Stroke is one of the primary causes of morbidity and death worldwide. While intravenous (IV) thrombolysis with alteplase has been widely proven to be beneficial for acute ischemic stroke patients, it still has many limitations. Tenecteplase, a revised version of alteplase, is a potential alternative IV thrombolytic agent that has benefits over alteplase. The aim of this mini-review is to summarize the advancements in IV thrombolysis for severe ischemic stroke, specifically the development and transition from alteplase to tenecteplase.