Stroke is a complex disease comprising of a heterogenous group of disorders with multiple risk factors. Genetic predisposition to stroke does occur and has been documented in both animal models and human beings. However, a precise definition of genetic factors responsible for stroke is still lacking because research into the genetic basis of stroke presents some unique challenges. More commonly it seems to be a multifactorial polygenic disorder. Mutations in some candidate genes are likely to predispose or give protection against stroke. Several mutations in various genes have been found to be associated with stroke. However, we have a long way to go before we can accurately pinpoint the genes responsible for multifactorial stroke. Recently, the deCODE group has suggested an association between the phosphodiesterase 4D (PDE4D) gene and the risk of stroke in Icelanders. PDE4D is the first putative gene associated with common polygenic stroke. Specific variants of this gene have been shown to present risk for ischemic stroke in Icelanders. Replication studies in non-Icelanders have yielded variable results. There may be obvious racial differences in the prevalence of these mutations but still many questions remain unsolved regarding the role of PDE4D in stroke development.