Vertebrate digits are essential structures for movement, feeding and communication. Specialized regions of the developing limb bud including the zone of polarizing activity (ZPA), the apical ectodermal ridge (AER), and the non-ridge ectoderm regulate the patterning of digits. Although a series of signaling molecules have been characterized as patterning signals from the organizing centers, the delicate cellular and molecular mechanisms that interpret how these patterning signals control the detailed digit anatomy remain unclear. Recent studies from model organisms and human hand malformations provide new insights into the mechanisms regulating this process. Here, we review the current understanding of the genetic networks governing digit morphogenesis.