Currently, intravenous thrombolysis is by far the most effective treatment of acute ischemic stroke, and its use can independently strongly increase the proportion of stroke patients surviving. While the use of recombinant tissue plasminogen activator in accordance to licensed criteria has continuously risen, off-label use is also frequent. In this review the most important reasons to transcend current license criteria are discussed and evidence is summarized from new studies, such as IST-3, contributing to the balance of increased benefit as opposed to possible harm in situations of off-label use of recombinant tissue plasminogen activator in stroke. In addition, several scores to predict risk and outcome in patients undergoing thrombolysis are compared.