Direct oral anticoagulants (DOAC), the factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and the direct thrombin inhibitor dabigatran, are emerging as anticoagulant treatment of choice for stroke prevention in patients with nonvalvular atrial fibrillation. Acute ischemic stroke occurs in 1% to 2% of DOAC-treated patients per year, and many would present within the standard therapeutic time window for intravenous thrombolysis and endovascular thrombectomy. This poses a significant clinical conundrum; it is likely that most patients with ischemic stroke taking DOACs are compliant with therapy, rendering the very medications used to prevent stroke the reason for withholding therapy. Current American Heart Association/American Stroke Association guidelines give a class III recommendation that thrombolysis might be harmful within 48 hours after last intake and should not be administered. Epidemiologic data published in 20211 suggest this may affect up to 18% of patients with atrial fibrillation who present with stroke1 who would be otherwise eligible for thrombolysis.