Early grafting experiments have indicated that ecto- and mesodermal tissues in limbs are not established independently but rather coordinately. This chapter emphasizes how the patterning of the limb is dependent on interactions between various signaling pathways emanating from the different spatial regions of the limb bud. It describes the role of the ectoderm and mesenchyme in the initial patterning of the three limb axes, as determined by transplantation experiments in the chick. The possible mechanisms that establish and maintain the organizing centers—apical ectodermal ridge, zone of polarizing activity, and the progress zone—are discussed. In doing so, the expression of known positional cues important for patterning the limb bud is described. However, a complete model remains to be determined for each axis whether the creation of a specific cell type in three-dimensional space is generated by competitive induction from opposing sides of the axis or whether there is a default cell type that can be repressed by an opposing signal. The chapter also describes significant research in limb development and models of axial patterning and provides insight into the future direction of vertebrate limb development.