Thrombolytic therapy with alteplase in acute ischemic stroke is currently established within 3 h from symptom onset in carefully selected patients. Expansion of the time window is being assessed in trials with alteplase and desmoteplase. Also, tenecteplase, reteplase and staphylokinase are being evaluated in stroke patients. A better understanding of the coagulation and fibrinolytic systems may provide insight into drug development, interactions, complications, and may ultimately improve patient triage and treatment regimens. Future adjuvant and additional therapies could prove useful for patients who do not benefit from standard thrombolytic treatment or may augment the overall gain.