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ABSTRACT The brain's collateral circulation consists of arterial anastomotic channels capable of providing nutrient perfusion to brain regions whose normal sources of flow have become compromised, as occurs in acute ischemic stroke. Modern CT‐based neuroimaging is capable of providing detailed information as to collateral extent and sufficiency and is complemented by magnetic resonance‐based methods. In the present era of standard‐of‐care IV thrombolysis for acute ischemic stroke, and following the recent therapeutic successes of randomized clinical trials of acute endovascular intervention, the sufficiency of the collateral circulation has been convincingly established as a key factor influencing the likelihood of successful reperfusion and favorable clinical outcome. This article reviews the features of the brain's collateral circulation; methods for its evaluation in the acute clinical setting; the relevance of collateral circulation to prognosis in acute ischemic stroke; the specific insights into the collateral circulation learned from recent trials of endovascular intervention; and the major influence of genetic factors. Finally, we emphasize the need to develop therapeutic approaches to augment collateral perfusion as an adjunctive strategy to be employed along with, or prior to, thrombolysis and endovascular interventions, and we highlight the possible potential of inhaled nitric oxide, albumin, and other approaches. This article is part of the Special Issue entitled ‘Cerebral Ischemia’. HighlightsThe brain's collateral circulation varies widely among individuals.Collateral circulation may be imaged spatially and temporally by CT angiography.Successful reperfusion in ischemic stroke is closely tied to the status of collateral circulation.Good collaterals lead to improved stroke outcome with thrombolytic and endovascular therapy.Agents that augment collateral circulation in acute stroke patients should be developed.Inhaled nitric oxide, and high‐dose albumin, may hold promise as collateral therapeutics.