Despite recent advances in understanding the molecular biology of lung carcinoma and the introduction of multiple new chemotherapeutic agents for its treatment, its dismal five-year survival rate ( < 15%) has not changed substantially. The lack of advancements in this area reflects the limited knowledge available concerning the factors that promote oncogenic transformation and proliferation of carcinoma cells in the lung. Tumor growth and invasion are not only the result of malignant transformation, but also depend on environmental influences from their surrounding stroma, local growth factors, and systemic hormones. In particular, the composition of the extracellular matrix is believed to affect malignant behavior in vivo. This document reviews information that implicates the matrix glycoprotein fibronectin in regulation of lung carcinoma cell proliferation, apoptosis and resistance to therapy. Fibronectin is highly expressed in chronic lung disorders where most lung carcinomas are identified. Data available to date indicate that by binding to specific integrin receptors expressed on tumor cells, fibronectin stimulates a number of intracellular signals implicated in the pathobiology of lung carcinogenesis including GTPases, mitogen-activated protein kinases, and the PI3-Kinase/Akt/mTOR pathway. Targeting fibronectin and integrin-mediated signals in tumor cells represents a promising target for the development of effective anti-cancer strategies.