Two issues have held the focus of thrombolysis research for over 50 years, namely, choosing between a plasminogen activator (PA) or plasmin as the best therapeutic agent and choosing between systemic or local administration. The original plasmin product of the 1950s was both ineffective and contaminated with PA, and catheter technology was not yet developed for routine clinical use. For decades, clinical practice has focused on PA and systemic administration, but today, PAs are often administered by catheter into thrombosed vessels, notably for peripheral arterial and graft occlusion and deep vein thrombosis, and increasingly for acute ischaemic stroke. Despite using catheter-delivered therapy, bleeding complications still occur, most severely expressed as symptomatic intracranial haemorrhage. New experimental data indicate that we should now reconsider plasmin as a viable, even preferable, thrombolytic agent. Plasmin requires catheter delivery to achieve thrombolysis, but this technical issue has been solved with modern technology and widespread presence of interventional suites. After local administration, plasmin will lyse thrombi; thereafter, any plasmin in the circulation will be rapidly neutralised. Pre-clinical studies confirm that plasmin has marked haemostatic safety advantage over t-PA. After more than 50 years, the field has come full circle, and plasmin as the thrombolytic agent and catheter use for local delivery of agent may represent a step forward in thrombolytic therapy.