The results of cisplatin-based chemotherapy seem to have reached a plateau, and empirical approaches are targeting the inclusion of novel biological agents with different mechanisms of action, but their clinical benefit is still unknown. In preparing this review of cisplatin resistance, we posed two questions: Who are we writing for and why? We believe that medical oncologists should be involved in the reality of the growing list of genetic mechanisms of cancer and chemoresistance. Only by becoming familiar with these mechanisms will we be able to circumvent them. In this review, we provide some insight into DNA repair defects involved in non-small-cell lung cancer (NSCLC) and cisplatin effect. Some DNA repair genes, like ERCC1, have been shown to be crucial in predicting cisplatin resistance and can be used for tailoring cisplatin-based chemotherapy.