A wealth of data indicates that certain genetic abnormalities can target specific cytotoxic drugs and intervene at an early step as a mechanism of resistance in the treatment of non-small-cell lung cancer. Therefore prescribing certain combinations of cytotoxic anticancer agents to a vast majority of these patients is futile. Genetic abnormalities have been found to be useful surrogate markers for response, particularly in colorectal cancer: thymidylate synthase mRNA and ERCC1 mRNA levels. In addition, beta-tubulin mutations may also confer paclitaxel resistance in patients. An important target to be explored for gemcitabine resistance is the assessment of a particular region in chromosome 11p15.5 wherein lies the ribonucleotide reductase gene that could affect gemcitabine metabolism. Shedding light on this genetic framework, several proposed customized chemotherapy studies could help validate the relevance of these markers.