Pharmacogenetics (PGx) in clinical practice is a tool that the clinician can use to guide, in a personalized way, the most suitable treatment that will be administered to the patient. The objective of this review is to summarize in a practical and accessible rational way, the advances that currently exist for the application of PGx in colorectal cancer chemotherapy management through the study of the patients’ germline polymorphisms. To define the polymorphisms that can be applied, we rely on three fundamental cornerstones: the recommendations of drug regulatory agencies; the implementation guidelines prepared by expert consortia in PGx and information from clinical annotations (the drug/polymorphism relation) according to the scientific level of evidence assigned by PharmGKB experts.