Stroke is a common entity. It is the third leading cause of death and the leading cause of adult disability in the developed world. More than 110 heritable disorders, more than 175 genetic loci, and more than 2050 unique mutations predisposing to stroke are known. Although ischemic stroke can result from merely one gene defect (and a number of clearly defined mendelian hereditary disorders do lead to stroke), the interaction of unfavorable genetic factors such as the Leiden V, methylenetetrahydrofolate reductase (MTHFR) 677TT, apolipoprotein E (ApoE) 4, and angiotensin-converting enzyme (ACE) D/D genotypes, which alone are not major risk factors, can in specific patterns exert a synergistic effect on certain clinical risk factors. This chapter discusses how to evaluate these interactions and the interpretation of findings.