Platinum compounds play a central role in cancer chemotherapy. Although treatment is limited by side effects, they continue to have widespread application. One of the main aims of clinical or translational research in cancer is the search for genetic factors that could foresee treatment outcomes, in biologic activity and toxic effects. This genetic analysis might allow selection of patients who will have the greatest benefit from chemotherapy. Furthermore, a better knowledge of the underlying molecular profile of the host and the tumor will facilitate screening for lung cancer susceptibility and tailoring of chemotherapy in individual patients, choosing those most likely to respond, adjusting doses more precisely in order to reduce less adverse effects, and establishing safety profiles based on individual genetic analyses. Herein, we discuss current knowledge regarding gene expression and polymorphisms of DNA repair enzymes in regard to cancer susceptibility and response to chemotherapy.