CYP2C9 is one of the most important and abundantly expressed enzymes of the cytochrome P450 system in the human liver. It is responsible for the metabolism of approximately 15 % of clinically important drugs, including coumarin anticoagulants (warfarin), anticonvulsants (phenytoin, valproic acid), oral antidiabetic agents (gliclazide, tolbutamide), angiotensin II receptor antagonists (candesartan, losartan), nonsteroidal anti-inflammatory drugs (NSAIDs), fluvastatin and siponimod. CYP2C9 gene is highly polymorphic and, to this day, over 60 different alleles have been identified, among which at least 20 have been proven to alter its gene product activity, which contributes to significant inter-individual variability of therapeutic response. Due to the decreasing effect on enzyme activity and the relatively high prevalence in Caucasians, CYP2C9*2 and CYP2C9*3 are the most important haplotypes. These alleles result in reduced metabolism for most CYP2C9 substrates, increased drug exposure, and consequently increased risk of adverse drug reactions, especially when administered drugs have a narrow therapeutic index. To identify individuals with increased risk of adverse drug reactions (ADRs) even before the treatment initiation, preemptive CYP2C9 genotyping is performed, and metabolic phenotype is inferred based on these results. There are three possible CYP2C9 phenotypes: poor metabolizer (PM), intermediate metabolizer (IM), and normal metabolizer (NM). In the Caucasian population, poor metabolizers make 3-5 %. This personalized approach enables in time selection of appropriate therapy and a better outcome for a patient. In this paper, current knowledge on the influence of CYP2C9 gene variations on the efficacy and safety of drugs metabolized by the CYP2C9 enzyme and a practical approach to validation of methods for CYP2C9 genotyping in clinical practice is presented.