The mechanisms mediating the proliferative effects of gastrointestinal (GI) peptide hormones and their cognate G protein-coupled receptors are associated intimately with epidermal growth factor (EGF) receptor-regulated signaling pathways. Although transactivation of the EGF receptor is now recognized as a critical component in GI peptide hormone regulation of mitogenic signaling and cell migration, their interactions are far more complex and include potentiation of intracellular signaling pathways, regulation of ligand expression and release, and modulation of cell surface receptor expression. Mitogen-activated protein kinases play a central role integrating the signals from these receptor systems. This review summarizes the mechanisms that intertwine GI peptide hormone receptor- and EGF receptor-activation and functions.