Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among t h e m, h e p a t o c y t e g r o w t h f a c t o r( H G F) / c- M E T, phosphoinositide 3-kinase(PI3K)/Akt/mammalian target of rapamycin(m TOR) and janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase Ⅲ studies of selective anti-HGF/c-MET antibodies and m TOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase Ⅰ studies, and phase Ⅲ evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase Ⅱ study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways. Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor r (HGF) / c-MET, phosphoinositide 3-kinase (PI3K) / Akt / mammalian target of rapamycin TOR) and janus kinase 2 / signal transducer and activator of transcription 3 (JAK2 / STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. including programmed cell death-1 / programmed cell death ligand-1 (PD-1 / PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of However, phase III studies of selective anti-HGF / c-MET antibodies and m TOR inhibitor failed to show signi ficant benefits in terms of overall survival and progression-free survival. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link effectively inhibit STAT3 activity. Inhibition of PD-1 / PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to Identify good responders. Regorafenib has promising sustenance in prolonging progression-free survival in a phase Ⅱ study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways.