Lung cancer is a common disease with more than 1.6 million new cases diagnosed worldwide in 2008. Treatments for patients with advanced disease are rarely curative, and responses to therapy are often followed by relapse, which highlights the large unmet need for novel therapies. Recent advances in cancer treatment have focused on personalized therapy, whereby patients are treated with agents that best target the molecular drivers of their disease. Thus, a better understanding of the pathways that drive cancer or drug resistance is of critical importance. One such example is the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which is activated in many lung cancer patients and represents a target for therapy. PI3K/AKT/mTOR pathway activation has also been observed in tumors resistant to agents targeting upstream receptor tyrosine kinases. Agents that target this pathway have the potential to shut down survival pathways, and are being explored both in the setting of pathway-activating mutations and for their ability to restore sensitivity to upstream signaling targeted agents. Here, we examine the frequency of mutations activating the PI3K/AKT/mTOR pathway, review the novel agents being explored to target this pathway, and explore the potential role of the inhibition of this pathway in the clinical development of these agents.