Computed tomography and magnetic resonance imaging of the brains of elderly individuals frequently show areas of altered signal intensity in the periventricular and subcortical white matter, referred to as leukoaraiosis. Although mildly affected individuals appear asymptomatic, larger burdens of leukoaraiosis are associated with deficits of cognition and gait. Histopathologically, areas of leukoaraiosis invariably show sclerosis, luminal narrowing, and tortuosity of small arteries and arterioles, accompanied by variable degrees of gliosis, demyelination, and axonal loss resulting from ischemia. Genetic variation plays a substantial role in interindividual differences in the volume of leukoaraiosis and its associated adverse clinical outcomes. Characterizing genetic factors contributing to interindividual differences in leukoaraiosis has the potential to enhance understanding of molecular determinants of ischemic brain injury and lead to new approaches to the diagnosis, evaluation, treatment, and prevention of this common form of vascular dementia.