The quest for markers of sensitivity to cytotoxic agents has been ongoing for decades. In non-small-cell lung cancer, platinum compounds represent the cornerstone of systemic therapy. They target DNA and induce damage that cancer cells struggle to overcome. Somatic excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), and ribonucleotide reductase M1 (RRM1) expression levels have been extensively explored as markers of DNA repair capacity in tumor cells. Although low ERCC1 and/or RRM1 expression is generally associated with sensitivity to platinum, the results published in retrospective and prospective studies are not always consistent. Against this background, we will examine in this review the function of these two biomarkers as well as the tools available for their assessment and the associated technical issues. Their prognostic and predictive values will be summarized and considered in terms of customizing systemic therapy according to biomarker (ERCC1 and RRM1) expression levels. We will also discuss why the use of both markers should at this point be restricted to clinical research and underline that functional readouts of DNA repair will help boost future strategies for biomarker discovery in the field.