A nascent understanding of metformin's biological effect on malignant cells may provide explanation to the aforementioned preclinical and clinical observations and solidifies the basis for further clinical exploration. Preclinical models suggest a variety of mechanism including inhibition of "energy sensing" pathways involved in cellular growth, interference with the IGF1-insulin axis and blockade of VEGF. Metformin is thought to activate AMP-activated protein kinase (AMPK), a major sensor of cellular energy levels and a key enzyme limiting cellular growth during times of cellular stress. Once activated, this enzyme restricts anabolic processes such as protein, cholesterol and fatty acid synthesis and inhibits mTOR, a protein kinase responsible for dysregulated growth. MTOR is upregulated in a variety of tumors, including NSCLC providing rationale to exploit this pathway with metformin. Secondly, metformin reverses hyperinsulinemia leading to down regulation of insulin-like growth factors (IGFs). These factors are associated with malignant and non-malignant tumorogenesis via their aberrant activation of PI3K/Akt pathway, a well known pathway that contributes to tumorigenesis. Finally, metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis, known as the Warburg effect, is a hallmark of cancer cells that constitutes an undisputed advantage in tumor growth. Despite this glycolytic shift, some malignant cells retain the capacity to continue oxidative phosphorylation for energy production which may enhance malignant potential. In vivo models indicate that metformin inhibits mitochondrial complex I thereby suppressing oxidative phosphorylation which may force cells to engage in survival processes like autophagy leading to eventual cell death. In summary, metformin's inhibition of tumor cell growth by disrupting both the MTOR and insulin pathways by AMP kinase activation represents a novel way to treat lung cancer.