In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra- and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase ADAM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17–AREG–EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.