Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock:(1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects;(2) complexity of stroke pathobiology: therapy must acknowledge the ‘Janus-faced’nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms;(3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system;(4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought;(5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.