Neuroprotection for acute ischemic stroke has undergone intense research for more than half a century, but has yielded no therapeutic application and remains an elusive goal. Detailed studies of the ischemic cascade conducted to date appear to have ignored the fundamental role of collateral circulation in the pathophysiology of ischemic stroke. Vascular aspects of neuroprotection and collateral dependence are becoming increasingly apparent following the refinement of multimodal imaging and improvements in the options for revascularization. Collateral perfusion demarcates the ischemic penumbra, influences drug delivery and alters clinical outcome. As outlined in this review, combined revascularization and neuroprotection that take into consideration the collateral perspective may ultimately determine the fate of neuroprotection in acute ischemic stroke.