Monoclonal antibodies and tyrosine kinase inhibitors against ErbB receptors have been developed and have progressed to clinical applications following several decades of research in cancer cell biology. Inhibition of epidermal growth factor receptor (EGFR) signaling represents a particularly promising arena for the application of molecularly targeted cancer therapies. In EGFR signaling inhibition, EGFR itself has been recognized as a target in epithelial malignancies, though clinical studies using EGFR antagonists have not always resulted in favorable clinical outcomes. The aberrant enhancement of EGFR ligand expression is speculated to be one of several different molecular mechanisms accounting for the acquired resistance to EGFR antagonists. Recently, emerging evidence has indicated that EGFR ligands deserve considerable attention as potential targets for cancer therapy. In this review, we discuss the EGFR signaling inhibition strategies directed at EGFR ligands such as HB-EGF and amphiregulin.