Stroke therapy has entered a new era highlighted by the use of endovascular therapy in addition to intravenous thrombolysis. However, the efficacy of current therapeutic regimens might be reduced by their associated adverse events. For example, over-reperfusion and futile recanalization may lead to large infarct, brain swelling, hemorrhagic complication and neurological deterioration. The traditional pathophysiological understanding on ischemic stroke can hardly address these occurrences. Accumulating evidence suggests that a functional cerebral venous drainage, the major blood reservoir and drainage system in brain, may be as critical as arterial infusion for stroke evolution and clinical sequelae. Further exploration of the multi-faceted function of cerebral venous system may add new implications for stroke outcome prediction and future therapeutic decision-making. In this review, we emphasize the anatomical and functional characteristics of the cerebral venous system and illustrate its necessity in facilitating the arterial infusion and maintaining the cerebral perfusion in the pathological stroke content. We then summarize the recent critical clinical studies that underscore the associations between cerebral venous collateral and outcome of ischemic stroke with advanced imaging techniques. A novel three-level venous system classification is proposed to demonstrate the distinct characteristics of venous collaterals in the setting of ischemic stroke. Finally, we discuss the current directions for assessment of cerebral venous collaterals and provide future challenges and opportunities for therapeutic strategies in the light of these new concepts.