The present invention features human epidermal receptor (HER) antagonists. These antagonists are polypeptide variants of ligands of HER. The HER ligand polypeptide variants of the invention possess Pan-HER antagonistic properties and can inhibit at least one HER-mediated biological activity of one or more HER subtypes, such as inhibition of the receptor's kinase activation activity and subsequently, cell proliferation. Such polypeptide variants, and nucleic acids encoding these polypeptide variants can be used therapeutically in situations in which inhibition of HER activity is indicated.