Objectives: This thesis aim is to systematically and clearly present the pharmacogenetics of 5-fluorouracil (5-FU) and DPYD gene polymorphisms that affects the efficacy and safety of 5-FU therapy. Healthcare professionals would find it easier to decide whether to reject or select and individualize 5-FU therapy according to the specific genotype of an oncology patient in need of 5-FU treatment, thus providing the safe treatment and prevention of severe side effects and death. Materials and methods: The scientific literature in databases Medline and PubMed in the last 10 years has been searched. Publications of professional associations and institutions, drug databases and other scientific sources also were searched. Therapeutic guidelines for the application and individualization of 5-FU therapy are commented (the most important polymorphisms of the DPYD gene c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A). The possible importance of other DPYD polymorphisms (c.496A>G, c.85T>C and c.2194G>A) is also described, and interethnic and interracial differences in the frequency of some DPYD polymorphisms are listed. Information on laboratories that perform DPYD genotyping and the possibilities of individualization of 5-FU therapy in Croatia are also presented. Results: DPD activity is a limiting factor in the rate of 5-FU metabolism and is subject to high variability, therefore patients with DPD deficiency are at increased risk of toxicity related to fluoropyrimidines. Guidelines for DPYD genotyping and fluoropyrimidine dosing were published by CPIC (Clinical Pharmacogenetics Implementation Consortium), which include 4 variants that have been shown to reduce DPD activity (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G A). Other polymorphisms (c.496A>G, c.85T>C and c.2194G>A) have been studied in various studies and most of the results speak in favor of reduced activity of DPD enzymes due to their presence. In the Italian randomized study Three or six colon adjuvant (TOSCA), serious and severe side effects were reported in 38.2 % of subjects (carriers of mutations c.2194G˃A, c.1905+1G˃A and c.496A˃G). Clinical trial Pan-European Trials in an Alimentary Tract Cancer (PETACC-8) also confirms the above mentioned as it was found that serious side effects occurred in 85.7 % of carriers of mutation c.2846A˃T and 60.8 % of carriers of mutation c.2194G˃А. Božina and co-workers reported serious side effects in 56.3 % of subjects (carriers of c.496A>G or c.2194G>A) while c.85T>C mutation was not associated with the development of serious side effects. The work of Henricks and co-workers has shown that pre-therapy testing is cost-effective or at least does not represent an additional cost to the health care system. Conclusion: Carriers of DPYD inactivating alleles have a significantly higher risk of serious side effects. Therefore, recommendations have been issued to perform genetic testing for DPYD or to measure DPD activity prior to drug administration. This facilitates the decision on the choice of 5-FU and dose individualization according to the patient's genetic profile and reduces health care costs because it improves treatment and reduces risks that represents suffering for the patient and cost the health system.