Ischemic stroke is a complex genetic disorder, diverse in pathophysiology and clinical presentation. This phenotypic diversity may reflect genotypic diversity. One approach to discovering genetic risk factors has been to study intermediate phenotypes as in carotid intima-media thickness and leukoaraiosis. Intermediate phenotypes can be highly heritable, assessed in stroke-affected and unaffected individuals, and analyzed as quantitative traits. Because there is not a one-to-one relationship between intermediate phenotypes and ischemic stroke, polymorphisms or haplotypes associated with an intermediate phenotype should be validated as risk factors for stroke itself. A complementary approach to gene discovery has been to fractionate the ischemic stroke phenotype into more homogeneous subphenotypes. Family history studies suggest that some subphenotypes like cardioembolic stroke may be less heritable than others.