As one of the leading causes of death within both the developed and developing world, stroke is a worldwide problem. Risk factors can be identified and controlled at the level of lifestyle changes; however, genetic components of stroke have yet to be identified. The identification of such genetic components is critical in the understanding, diagnosis, and treatment of stroke in the future. This review focuses on the genetic determinants of stroke in both human and experimental systems. Mendelian disorders, candidate genes, and twin studies provide evidence for a strong genetic component of stroke. Genome-wide scanning in both human and animal models has led to the identification of regions of the genome that contain genes for stroke susceptibility and sensitivity. Animal models of stroke allow for environmental control and genetic homogeneity, not possible within a human population, and therefore are essential for the dissection of this complex, multifactorial disorder. Future genetic and genomic strategies and their role in ultimate causative gene identification are discussed.