The quest for disease genes that confer risk for stroke is now being undertaken using three complementary approaches. Positional cloning using rare Mendelian phenocopies of stroke has found genes that contribute to rare forms of stroke but, so far, not to the common forms of stroke. Candidate-gene case-control association studies using the common forms of stroke have found suggestive associations of modest effect. However, positional cloning using hundreds of Icelandic families affected by the common forms of stroke has recently found two genes conferring substantial risk for ischemic stroke that have apparently been confirmed in the USA and other European populations. Both genes encode enzymes, phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (FLAP), which suggest novel treatment strategies for stroke prevention.