Lung cancer is the leading cause of cancer-related mortality in the world, with more than 1 million deaths per year. Over the past years, lung cancer treatment has been based on cytotoxic agents and an improvement in the outcome and quality of life for patients has been observed. However, it has become clear that additional therapeutic strategies are urgently required in order to provide an improved survival benefit for patients. Two major intracellular signaling pathways, the Ras/Raf/extracellular signal-regulated kinase (Erk) and the phosphoinositide 3-kinase (PI3K)/Akt pathways have been extensively studied in neoplasia, including lung cancer. Furthermore, the study of constitutively activated receptor tyrosine kinases (RTKs) and their downstream signaling mediators has opened a promising new field of investigation for lung cancer treatment. Since both the Ras/Raf/Erk and the PI3K/Akt pathways are downstream of a plethora of activated RTKs, they have been extensively studied for the development of novel anti-tumor agents. Moreover, the mammalian target of rapamycin (mTOR) has been identified as a downstream target of the PI3K/Akt pathway. Rapamycin and its derivatives are highly selective and very potent inhibitors of mTOR and initial pre-clinical and clinical studies have reported encouraging results for different tumor types. Nevertheless for lung cancer, this approach has not been successful yet. Here we will review the molecular basis of PI3K/Akt/mTOR signaling in lung cancer and further discuss the therapeutic potential of multi-targeted strategies involving mTOR inhibitors.