In order to further define the mechanisms by which polypeptide growth factors regulate gene transcription and cellular growth, expression cloning techniques were used to select human epidermal growth factor (EGF) receptor complementary DNA clones. The EGF 3' coding domain shows striking homology to the transforming gene product of avian erythroblastosis virus (v-erbB). Over-expression of EGF receptors in A431 cell lines correlates with increased EGF receptor mRNA levels and amplification (up to 110 times) of the apparently singular EGF receptor gene. There appear to be three cytoplasmic polyadenylated RNA products of EGF receptor gene expression in A431 cells, one of which contains only 5' (EGF binding domain) sequences and is postulated to encode the secreted EGF receptor-related protein.