Pharmacogenomic analyses will become crucial to predict patients' toxicity to treatment and will also help to predict the tumor response. Processes of drug metabolism, drug efflux, DNA-repair and characteristics of drug targets are critical checkpoints of drug efficacy. These crucial pathways for drug action have been part of pharmacogenomic studies evaluating the impact of genomic variants on transcription, translation, protein structure and substrate binding of the genes involved. Promising candidates have been identified with predictive value for response and toxicity to chemotherapy in colorectal cancers. These candidates need to be incorporated into large, prospective clinical trials to confirm their impact for response and survival to chemotherapy that has been reported in retrospective analyses. Confirmed predictive markers, together with additional yet to be identified pharmacogenomic key players, will provide the basis for tailoring chemotherapy in the future.