Numerous growth factors and receptors that alter proliferation have been identified in lung cancer. In non-small cell lung cancer (NSCLC) cell lines, high levels of vasoactive intestinal peptide (VIP) mRNA have been detected by Northern analysis, and immunoreactive VIP is present. VIP elevates intracellular cAMP and stimulates the clonal growth of NSCLC cells. Also, transforming growth factor alpha (TGF-alpha) mRNA is present in NSCLC cells and TGF-alpha is present in conditioned media exposed to NSCLC cells. TGF-alpha binds with high affinity to epidermal growth factor (EGF) receptors present on NSCLC cells. EGF stimulates tyrosine kinase activity and growth in NSCLC cells. Synthetic peptide antagonists and monoclonal antibodies have been identified that disrupt autocrine growth pathways and inhibit NSCLC growth. These data suggest that VIP and TGF-alpha are important autocrine growth factors for NSCLC.