Nitric oxide (NO) generated by endothelial NO synthase (eNOS) plays a crucial role in vascular function and homeostasis. NO possesses vasodilatory, anti-inflammatory, antithrombotic and antiproliferative properties. Augmentation of NO production increases cerebral blood flow, which can lead to neuroprotection during brain ischaemia. Several modalities that upregulate eNOS expression and/or activity have recently been identified, including HMG-CoA reductase inhibitors (statins), steroid hormones, nutrients and physical activity. They all increase NO bioavailability, leading to enhanced cerebral blood flow and protection from ischaemic stroke. Thus, therapeutic modalities that target eNOS not only serve as preventive measures to reduce stroke incidence but also could represent novel treatment strategies for reducing brain injury during cerebral ischaemia.