Small cell lung cancer (SCLC) is a difficult disease to treat and sometimes has overexpression or mutation of c-Met receptor tyrosine kinase. The effects of c-Met/HGF (ligand for c-Met) on activation of reactive oxygen species (ROS) was determined. HGF stimulation of c-Met overexpressing H69 SCLC cells (40ng/ml, 15 minutes) resulted in an increase of ROS, measured with fluorescent probe 2'-7'-dichlorofluorescin diacetate (DCFH-DA) or dihydroethidine (DHE) but not in c-Met null H446 cells. ROS was increased in juxtamembrane (JM)-mutated variants (R988C and T1010I) of c-Met as compared to wild-type c-Met expressing cells. ROS was significantly inhibited by preincubation of SCLC cells with PDTC (pyrrolidine dithiocarbamate, 100 µM) and/or SU11274 (small molecule c-Met tyrosine kinase inhibitor, 2 µM) for 3 hrs. PDTC and SU11274 also abrogated the HGF proliferative signal and cell motility in a cooperative fashion. H₂O₂ treatment of SCLC cells (over 15 min) led to phosphorylation of c-Met receptor tyrosine kinase, and further up-regulated downstream phosphorylation of phospho- AKT, ERK1/2 and paxillin in a dose dependent manner (125µM to 500µM). c-Met is an important target in lung cancer and the pathways responsible for ROS generation together may provide novel therapeutic intervention.