Lung cancer is a worldwide problem. At the time of diagnosis, 50% of patients have advanced incurable disease. Different chemotherapy combinations — with or without targeted therapies — yield similar results despite the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes, whereas thioredoxin confers a broad spectrum of chemoresistance. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival in certain cisplatin-based regimens. Epidermal growth factor receptor tyrosine kinase mutations are the crux of targeted therapies, whereas epithelial–mesenchymal transitions and HER3 mRNA levels are promising ancillary markers for treatment with epidermal growth factor receptor tyrosine kinase inhibitors.