Considerable evidence suggests genetic factors are important in the pathogenesis of multifactorial stroke. However, studies identifying the underlying genes have been largely disappointing. This chapter reviews the different approaches and their relative merits. It is likely stroke is a polygenic disorder and that underlying genes may interact within environmental risk factors. Stroke itself is a syndrome caused by a number of different pathologies, which may result from different genetic predispositions. Therefore accurate stroke subtyping is likely to be important in identifying genetic associations. Previous studies have suffered from small sample size, lack of adequate phenotyping, and poor case-control matching. The most popular approach to identifying genes in human polygenic ischemic stroke has been the candidate gene approach. The relative merits of this approach are discussed. More recently this has been extended to famly-based association studies. Linkage-based approaches have been used less although current studies are implementing the affected-sibling-pair method. In the future genome-wide association studies are likely to become more widely used.