The treatment of advanced non-small-cell lung cancer (NSCLC is based on the combination of platin and one of the following agents: taxanes, gemcitabine, vinorelbine or irinotecan. There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.