Lung cancer is the number one cause of cancer-related mortality. In order to improve the outcome of patients, advances in the understanding of cancer biology and the development of therapeutic modalities that target key proliferation and survival mechanisms are needed. In vitro data have demonstrated that the genes RRM1 and ERCC1 are important components of these mechanisms. Recently, how these genes affect lung cancer therapy has been explored in the clinical setting with the goal of finding customized treatment algorithms to optimize efficacy, improve outcomes and minimize toxicity.