Fluoropyrimidines (5-fluorouracil, capecitabine) are the mainstay chemotherapeutic agents for the treatment of many types of cancer. Metabolism of fluoropyrimidines requires dihydropyrimidine dehydrogenase (DPD encoded by the DPYD gene) and reduced or absent activity of this enzyme can result in severe and sometimes fatal toxicity. Evidence and therapeutic recommendations are presented for DPYD genotype-directed dosing of fluoropyrimidines. This document is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for DPYD genotype and fluoropyrimidine dosing (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/).