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Major advances in understanding growth factor biology, especially in epithelial cells, have resulted from work with TGF-alpha over the past decade. It is clear that TGF-alpha is a potent epithelial oncoprotein, but equally important biological activities in normal epithelial homeostasis have been described. A number of major challenges lie ahead. Foremost is the formidable task of dissecting out the individual contributions of each EGF-related peptide in the biological response to stimulation of the EGFR. Appreciation of the complexity of heterodimerization of receptors within the EGFR family will be equally important in the final analysis. These considerations assure the continued vitality and productivity of investigation of the EGF-related peptide/EGFR axis.