Symptomatic lacunar ischemic stroke (25% of all brain infarctions) results from occlusion of a single penetrating artery by microatheromas or lipohyalinosis and rarely from an intracranial atheromatous branch disease. Recurrent lacunar stroke may be associated with more severe clinical features and has been involved in producing lacunar state and vascular subcortical dementia. In the first multicenter randomized clinical trial (SPS3) focused on stroke prevention among patients with recent lacunar stroke, the addition of clopidogrel to aspirin not only did not reduced significantly the risk of recurrent stroke, but also increased significantly the likelihood of hemorrhage and fatal outcome. If lacunar stroke is primarily non-atherothromboembolic, secondary prevention aimed at preventing atheroma progression may not be very effective. The efficacy of drugs that improve endothelial function in lacunar stroke patients remains to be studied in the future.