Links between cancer and metabolism have been suggested for a long time but compelling evidence forthis hypothesis came from the recent molecular characterization of the LKB1/AMPK signaling pathway as atumor suppressor axis. Besides the discovery of somatic mutations in the LKB1 gene in certain type of cancers,a critical emerging point was that the LKB1/AMPK axis remains generally functional and could be stimulatedby pharmacological molecules such as metformin in cancer cells. In addition, AMPK plays a central role in thecontrol of cell growth, proliferation and autophagy through the regulation of mTOR activity, which is consistentlyderegulated in cancer cells. Targeting of AMPK/mTOR is thus an attractive strategy in the development oftherapeutic agents against non-small-cell lung cancer (NSCLC). In this review, the LKB1/AMPK/mTOR signalingpathway is described, highlighting its protective role, and opportunities for therapeutic intervention, and clinicaltrials in NSCLC.