Pharmacogenetics (PGx) plays a critical role in optimizing drug therapy by tailoring treatment based on individual genetic profiles, with the potential to improve clinical outcomes. Accurate data on allele and phenotype distributions in specific populations is essential for effective clinical application. This study presents the first comprehensive PGx landscape of the population in North Macedonia, using extended whole exome sequencing (WES) data. All individuals in the cohort had at least one aberrant phenotype across key pharmacogenes, consistent with global findings. Significant differences in haplotype frequencies were observed compared to broader European populations, underscoring the importance of region-specific PGx data. Of the 78 AMP-recommended alleles, 27 were identified, with all of participants carrying at least one Tier 1 allele. Compared to previous targeted studies in our population, WES enabled detection of lower-frequency AMP alleles and rare CYP2D6 variants not typically captured by local genotyping assays. Based on in silico functional impact predictions, 128 novel putative non-functional variants were identified across 19 pharmacogenes, including 17 in AMP-recommended genes such as DPYD, CYP3A4, and VKORC1—where novel variants were sometimes more frequent than those previously reported. These findings highlight the presence of additional clinically relevant variants beyond standard panels and emphasize the limitations of targeted genotyping. However, challenges remain, particularly for complex genes like CYP2D6, where short-read WES cannot fully resolve haplotypes. This study reinforces the need for improved sequencing methodologies and guidelines for interpreting novel PGx variants, while demonstrating the value of population-specific profiling to advance precision medicine and inform clinical practice.