There are seven ligands for the epidermal growth factor receptor (EGFR) ErbB1 and two ligands for ErbB3. EGFR can form a homodimer or a heterodimer with ErbB3. In this study, we investigated whether homodimers or heterodimers, and which ligand, playa major role in cancer development, with the goal of ultimately identifying therapeutic targets. We demonstrated that the ErbB3 ligand heregulin1 is the strongest mitogenic factor for non small cell lung cancer cells and is more potent in activating EGFRmut-ErbB3 heterodimers than EGFRwt-ErbB3 heterodimers. We discovered that four of the seven EGFR ligands inhibited heregulin1-induced EGFRwt-ErbB3 activation and cell proliferation by promoting dephosphorylation of heregulin1-induced ErbB3 phosphorylation, whereas the other three did not exhibit such inhibition. Importantly, those four EGFR ligands did not inhibit heregulin1-induced EGFRmut-ErbB3 activation and proliferation of cells with EGFR mutants. We demonstrated that ErbB3 was overexpressed in the lung cancer cells but not in the adjacent normal alveoli or stromal tissue. EGFR and heregulin1 were also highly expressed in lung cancer cells. We conclude that the overexpression of heregulin1, ErbB3, and EGFR mutant renders uncontrolled cell proliferation.