Stroke is thought to be a multifactorial disease that is affected by several environmental factors and genetic variants. In 2002, a candidate locus for stroke (STRK1) was identified with a significant logarithm of odds (LOD) score at 5q12 in Caucasians, and in 2003, the PDE4D gene was subsequently identified as a susceptibility gene at this locus. Some investigators have recently examined whether polymorphisms in the PDE4D gene are associated with stroke in population studies. Some of these studies have reported the polymorphisms to be associated with a risk of stroke, while others have reported the exact opposite. These discrepancies have been attributed to racial differences or differences in methodologies and analyses. In 2006, a powerful method for isolating the susceptibility region at 5q12 was reported in a haplotype-based case-control study. In the present paper, we review both current issues and progress in the isolation of susceptibility genes for ischemic stroke, with particular emphasis on the PDE4D gene in the STRK1 region of 5q12.