Non-small-cell lung cancer (NSCLC) accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. Most patients with NSCLC are diagnosed in the advanced stages, with the majority of patients presenting with Stage III or IV disease. Despite the introduction of more effective chemotherapeutic agents, it appears that a survival plateau has been reached. Thus, new treatment strategies are clearly needed. One such approach is the study of genes influencing drug activity, which offer the possibility of tailoring therapy according to the specific genetic profile of individual patients. Approximately 90% of lung cancer mortality among men and 80% among women is attributable to smoking. Cigarette smoking has been found to induce DNA damage. Lower DNA-repair capacities have been associated with a higher risk of lung cancer. Once cancer has been diagnosed, defective DNA-repair capacities can confer a favorable cytotoxic effect. The nucleotide excision repair system plays a major role in repairing a variety of distorting lesions, notably platinum-induced DNA adducts. The present review focuses on the excision repair cross-complementing (ERCC)1 which is the lead enzyme in the nucleotide excision repair process. Several groups have investigated the influence of ERCC1 on resistance to chemotherapy. Overall, the data suggest that ERCC1 is a marker for resistance to cisplatin. At present, molecular markers, such as ERCC1, represent a potential parameter to help guide clinical treatment decisions. Prospective pharmacogenomic studies are therefore a research priority in NSCLC.