Intravenous thrombolysis with alteplase is one of the few evidence-based acute ischemic stroke treatments. Efficacy is time dependent and not all patients treated within the 4.5 h license derive benefit. The lytic agent tenecteplase has theoretical benefits. In the Phase II study by Parsons and colleagues, tenecteplase was superior to alteplase across imaging and safety outcomes for patients selected using specific imaging criteria. We review the evidence for thrombolysis, experience with tenecteplase and compare this study with others that have used similar designs for the investigation of novel stroke lytic agents.