Current therapeutic strategies for acute ischemic stroke focus on vessel recanalization or penumbral neuroprotection without consideration of collaterals. Collateral circulation defines the extent of the ischemic penumbra, providing blood flow to tissues at risk of infarction downstream from an occluded artery. Therefore, leptomeningeal collaterals are a principal delivery route for oxygen, nutrients and potential therapeutic agents. Understanding of collateral anatomy and physiology is essential for the development of effective stroke treatments. Diagnostic imaging modalities may illustrate the penumbra from the collateral perspective, defining regions of relative ischemic vulnerability. Although specific collateral therapeutics are unrealized, insight may be gleaned from subtle details of prior stroke studies. Future advances will result from nascent research in therapeutic arteriogenesis and gene therapy adapted to the specific features of the cerebral circulation.