The phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) pathway is associated with all three major radiation resistance mechanisms: intrinsic radiosensitivity, tumor cell proliferation, and hypoxia. In cell signaling cascades, the PI3-K/AKT signaling pathway is a key regulator of normal and cancerous growth and cell fate decisions by processes such as proliferation, invasion, apoptosis, and induction of hypoxia-related proteins. Activation of this pathway can be the result of stimulation of receptor tyrosine kinases such as epidermal growth factor receptor or vascular endothelial growth factor receptor or from mutations or amplification of PI3-K or AKT itself which are frequently found in non-small cell lung cancer (NSCLC). Furthermore, several treatment modalities such as radiotherapy can stimulate this survival pathway. Monitoring and manipulation of this signal transduction pathway may have important implications for the management of NSCLC. Strong and independent associations were found between expression of activated AKT (pAKT) and treatment outcome in clinical trials. Direct targeting and inhibition of this pathway may increase radiosensitivity by antagonizing the radiation induced cellular defense mechanisms especially in tumors that have activated the PI3-K/AKT cascade. To successfully implement these treatments in daily practice, there is a need for molecular predictors of sensitivity to inhibitors of PI3-K/AKT activation. In conclusion, the PI3-K/AKT pathway plays a crucial role in cellular defense mechanisms. Therefore, quantification of the activation status is a potential parameter for predicting treatment outcome. More importantly, specific targeting of this pathway in combination with radiotherapy or chemotherapy may enhance tumor control in NSCLC by antagonizing cellular defense in response to treatment.