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Intravenous thrombolysis (IVT) has been the mainstay of acute ischemic stroke (AIS) treatment for over three decades. Recently, several studies have evaluated the safety and efficacy of IVT in certain complex clinical scenarios such as bridging IVT with mechanical thrombectomy (MT) versus direct MT, MT in distal medium vessel occlusions (DMVOs), and extended time window reperfusion. Many of these scenarios overlap with neurointerventional treatment strategies. This updated evidence has uncovered certain nuances in AIS treatment (transfer vs non-transfer patients, degree of disability, feasibility of MT) that warrant consideration in medical decision-making in addition to the conventional risks-versus-benefits discussion. Furthermore, as an increasing number of neurologists with diverse subspecialty interests are involved in AIS triage and treatment decision-making across various patient-care models (telestroke, spoke and hub systems, etc), variability in data interpretation may lead to inconsistencies in the administration of these time-sensitive therapies. In this vignette-based narrative review, we focus on evolving ‘gray zones’ of AIS reperfusion therapy that are particularly relevant to neurointerventional practice: (1) bridging IVT before MT, and (2) reperfusion strategies for DMVOs, with the role of IVT in the extended time window primarily discussed within the second vignette and, to a lesser extent, in the first. This paper is not meant to be a treatment guideline but rather a case-based exercise to provide a better understanding of the new data in this area.