Besides their well-documented function of reverse transport of cholesterol, high-density lipoproteins (HDLs) display pleiotropic effects due to their antioxidant, antithrombotic, anti-inflammatory and antiapoptotic properties that may play a major protective role in acute stroke, in particular by limiting the deleterious effects of ischaemia on the blood-brain barrier (BBB) and on the parenchymal cerebral compartment. HDLs may also modulate leukocyte and platelet activation, which may also represent an important target that would justify the use of HDL-based therapy in acute stroke. In this review, we will present an update of all the recent findings in HDL biology that could support a potential clinical use of HDL therapy in ischaemic stroke.