Early in vertebrate limb development, a program initiates that polarizes the limb along the antero-posterior axis. The mesenchyme at the posterior margin is ultimately responsible for the asymmetry due to a region called the zone of polarizing activity (ZPA). The ZPA produces and secretes the molecule SHH, which coordinates the patterning of the resulting digits. Preaxial polydactyly (PPD) is a commonly occurring limb abnormality; investigating the genetic basis of this defect has provided insights into our understanding of digit patterning. PPD disrupts limb asymmetry by producing an ectopic ZPA at the opposite margin of the limb bud. Mutations in the long-range, limb-specific regulatory element of the Shh gene are responsible for the defect. Genetic analysis of this limb abnormality provides an important approach in understanding the mechanisms that control digit patterning.