A rapidly increasing proportion of patients with acute ischemic stroke who are otherwise eligible for thrombolysis are excluded from this treatment because of possible or known concomitant direct oral anticoagulant (DOAC) treatment. Because the patient has had an ischemic stroke, the patient may not be effectively anticoagulated. The choice to either reverse the DOAC, followed by treatment with tissue plasminogen activator (tPA), or follow current American Heart Association/American Stroke Association guidelines1 and not treat the patient at all, if DOAC use is suspected within the past 48 hours, is not a decision for the faint of heart or the inexperienced. In the absence of a universally available rapid test to measure DOAC activity and the lack of standardized assay thresholds, the clinician who decides to treat must speculate on the coagulation status of the patient or consider blindly administering a costly and potentially risky reversal agent to treat the patient with a thrombolytic agent. Both reversing anticoagulation that has been prescribed for a prothrombotic or emboligenic condition and administering a thrombolytic to a patient receiving a DOAC are risky choices in which convincing data one way or the other are lacking and not likely to emerge from randomized clinical trials. Yet not reversing and treating may deprive the patient of the opportunity to escape long-term disability. There are many nuances to consider that would affect this decision. This Viewpoint will highlight several areas of uncertainty that a clinician must consider with thrombolysis treatment in patients exposed to DOACs.