Among hypertension-associated cardiovascular diseases, stroke represents one of the most common disorders. In fact, it significantly affects mortality and morbidity rates of all industrialized countries. Only recently, stroke has been considered as a complex trait and not as a mere consequence of hypertension. Indeed, it appears to be the result of an interaction among several genetic and environmental factors. The identification of the genetic determinants of stroke is a difficult task in humans, due to the genetic heterogeneity of human populations and the confounding presence of other risk factors. Thus, an experimental approach, through the use of a highly inbred animal model for stroke, offers a valuable alternative and additional support for a genetic dissection of cerebrovascular disease. In fact, the genetic analysis of stroke in the animal model of the stroke-prone spontaneously hypertensive rat provided clear evidence that stroke is a genetically determined complex trait, and that factors such as blood pressure and diet only play a permissive role. Finally, by using the experimental approach, we established that the gene encoding atrial natriuretic peptide, significantly linked to cerebrovascular disease in rats, is a genetic determinant of stroke in humans. The identification of the genetic basis of stroke represents an important step towards the institution of targeted preventive and therapeutic approaches to reduce the risks of cerebrovascular accidents. This article reviews the background, the experimental approach and the outcome of a strategy based on the use of the stroke-prone spontaneously hypertensive rat model, which aims at identifying the genetic basis of stroke.