Two proteins, termed epithelin 1 and epithelin 2, that inhibit the growth of A431 cells, derived from a human epidermal carcinoma of the vulva, have been purified from rat kidney. Epithelin 1 stimulates the proliferation of murine keratinocytes, whereas epithelin 2 inhibits the epithelin 1-elicited growth of these cells. Thus epithelin 1 and 2 behave as agonist and antagonist, respectively, for normal epithelial cells. Epithelins are low molecular mass (approximately 6 kDa), acid- and heat-stable, single-chain proteins containing approximately 20% cysteine. Some of these cysteines form disulfide linkage(s) that are essential for biological activity. The amino-terminal amino acid sequences of epithelin 1 and epithelin 2 have been determined. The two proteins showed no substantial sequence homology with other proteins. However, a significant homology was seen between the amino-terminal sequences of epithelin 1 and epithelin 2. Epithelins 1 and 2, therefore, appear to represent members of a distinct family of growth regulators.