Although drugs inhibiting ErbB receptors such as epidermal growth factor receptor (EGFR) and HER2 have been developed as anticancer agents targeting the EGF family, they are not effective for all types of cancer and instead target only certain types. We propose the following four main reasons for these observations: (i) although seven EGFR ligands exist, effective inhibition of specific EGFR ligands may occur because their expression levels differ in different malignancies; (ii) suppressing EGFR ligands inhibits aggregation of EGFR and other ErbB receptors and activation of ERK and Akt signals; (iii) EGFR ligands may have various combinations for signal transduction through the EGFR pathway and other receptor signals; and (iv) the intracellular C-terminals of EGFR ligands move into the nucleus and strongly regulate cell proliferation. In this review, we describe important implications for targeted cancer therapy against EGFR ligands and describe the current situation in the development of ligand-based therapies for cancer.