Abstract: We have recently established a mouse model of focal stroke under dual antiplatelet therapy (DAPT) to study tissue plasminogen activator (tPA)-associated hemorrhagic transformation. The purpose of this short perspective is to discuss the rationale for establishing the model, highlighting its relevance for addressing unresolved clinical questions. Hemorrhagic conversion of the ischemic stroke remains one of the major liabilities of thrombolytic therapy with tPA, contributing to unfavorable outcomes and failed regeneration. This was recognized early on, and the resulting restrictions on tPA usage have led to only a minor percentage of stroke patients receiving any kind of drug treatment to limit ischemic injury. Broadening the patient population eligible for thrombolytic therapy is a major goal, and thus efforts are being directed at optimally defining inclusion criteria based on prior drug treatment status, among other factors. DAPT with aspirin and clopidogrel (ASA + CPG) is commonly given to patients at high risk for atherothrombotic events. However, clinical data to date has not been entirely clear as to whether the increased likelihood of bleeding following thrombolysis in patients on DAPT is indeed detrimental to patient outcome, and many see this potential downside outweighed by the benefits of recanalization of the blocked vessel. Accordingly, current guidelines allow for tPA thrombolysis in patients under DAPT. Nonetheless, doubts remain if on balance tPA is actually beneficial in these patients, and these doubts may lead to undertreatment. Final clarity might be achieved with a prospective, randomized clinical trial, but it appears unlikely that this will ever occur. In this situation, modeling the process in animals subjected to experimental ischemic stroke under DAPT can provide insights into mechanisms of hemorrhagic transformation (HT). Even more importantly, establishing such a model enables researchers to test possible strategies to mitigate the bleeding risk in patients on DAPT. If the safety of tPA thrombolysis can be increased by reducing hemorrhage, this could clearly tilt the balance towards favoring tPA treatment, and thus improve long-term outcomes of ischemic strokes. Testing such an approach in the animal model is the best first step in evaluating the utility of such an adjuvant.