The expression of mammalian target of rapamycin (mTOR) might be upregulated by various mechanisms in lung cancer pathogenesis, and its activity might be modulated by pathways related to tobacco-mediated carcinogenesis. Furthermore, preclinical data suggest an antitumor effect in lung cancer from a class of agents that antagonize the mTOR pathway. Consistent with this, initial clinical trials of mTOR inhibitors suggest some activity in the setting of both non-small-cell lung carcinoma and small-cell lung carcinoma. Herein, we explore the relationship of mTOR to lung carcinogenesis and further describe clinical trials of mTOR inhibitors alone and in combination with chemotherapeutic and targeted agents.