The benefit of mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to large vessel intracranial occlusions is directly related to the technical success of the procedures in achieving fast and complete reperfusion. While a precise definition of refractoriness is lacking in the literature, it may be considered when there is reperfusion failure, long procedural times, or high number of passes with the MT devices. Detailed knowledge about the causes for refractory MT in AIS is limited; however, it is most likely a multifaceted problem including factors related to the vascular anatomy and the underlying nature of the occlusive lesion amongst other factors. We aim to review the impact of several key unfavorable anatomical factors that may be encountered during endovascular AIS treatment and discuss potential bail-out strategies to these challenging situations.