<p>Despite extensive research defining the molecular cascades of ischemic stroke, including excitotoxicity, oxidative stress, inflammation, blood–brain barrier disruption, and regulated cell death, translation of neuroprotective strategies into effective clinical therapies has remained largely unsuccessful. Growing evidence suggests that this gap reflects recurring limitations in translational design rather than insufficient mechanistic insight, including phase-inappropriate intervention, narrow therapeutic windows, inadequate brain exposure, and lack of target engagement in heterogeneous patient populations. In this review, we critically examine why biologically plausible targets have failed to produce clinical benefit by synthesizing lessons from preclinical and clinical studies. We identify common patterns of translational failure and propose a phase-resolved, biomarker-anchored framework that prioritizes therapeutic actionability according to disease stage and neurovascular context. By repositioning biomarkers as tools for patient stratification, risk prediction, and confirmation of target engagement, this framework supports rational sequencing from hyperacute reperfusion support to stage-matched neurovascular and immune modulation and subsequent neurorestorative strategies. This decision-oriented perspective aims to guide more effective trial design and improve translational success in ischemic stroke.</p>