Gene regulatory networks in developing organisms have been conserved during evolution. The Drosophila wing and the vertebrate hindbrain share the gene network involved in the establishment of the boundary between dorsal (D) and ventral (V) compartments in the wing and adjacent rhombomeres in the hindbrain. By means of a Systems Biology approach that combines a powerful mathematical modeling and both in silico and in vivo experiments in the Drosophila wing primordium, we have recently reverse-engineered and modeled such regulatory network. In this context, I present in vivo and in silico evidence that a novel property is required for the formation of a stable DV boundary: refractoriness to a signaling molecule. Such property modulates the regulatory interactions between species, promotes mutually exclusive domains of their activities, and confers stability to the DV boundary. Concepts like the spatiotemporal refinement of receptor activity and the polarized signaling between receptor and its ligands are also addressed and explained in terms of such refractoriness.