DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for catabolism of pyrimidine bases and fluoropyrimidine chemotherapy drugs 1. DPD catalyzes the reduction of uracil and thymine and is involved in degradation of the chemotherapeutic drug 5-fluorouracil 2. The enzyme functions as a homodimer and requires NADP+ and FAD as cofactors for its catalytic activity. Genetic variants in DPYD significantly impact DPD enzyme activity, with four clinically relevant variants (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A) used to calculate a gene activity score ranging from 0 (no activity) to 2 (normal activity) 1. DPD deficiency due to DPYD variants increases risk of severe, potentially fatal fluoropyrimidine-induced toxicity including diarrhea, hand-foot syndrome, mucositis, and myelosuppression 1. Prospective DPYD genotyping allows for personalized fluoropyrimidine dosing, with heterozygous carriers receiving 25-50% dose reductions depending on the variant 3. This genotype-guided approach significantly improves patient safety while maintaining treatment efficacy, with pooled survival analyses showing no negative impact on progression-free or overall survival 4. DPYD genotyping is now considered essential before initiating fluoropyrimidine therapy 1.