The Ras proteins are pivotal regulators of cellular proliferation, differentiation, motility, and apoptosis. Mutations on the K-ras gene have been found in 20%-30% of non-small-cell lung cancers and are believed to play a key role in this malignancy. Herein, we review the complex biochemical mechanisms through which K-ras exerts its cellular effects and the results from studies designed to evaluate the clinical importance of K-ras in patients with lung cancer. Since the demonstration of K-ras mutation as a negative prognostic marker 2 decades ago, 8 studies have supported this finding, but an equal number have failed to confirm this. There are also conflicting data for K-ras as a predictor of resistance to chemotherapy and radiation therapy. Progress has been hampered by relatively small studies, different methods of molecular analysis, and heterogeneity in histologic subtypes, stage, treatment administered, and survival criteria used. However, recent findings among patients treated with adjuvant chemotherapy or epidermal growth factor receptor inhibitors highlight that K-ras might yet be an important biomarker for non-small-cell lung cancer and worthy of further research.