Pharmacogenomics, at the intersection of genetics and medicine, promises personalized treatment strategies by deciphering how genetic variations influence drug response. This comprehensive review explores foundational principles, methods, clinical applications, challenges, and future perspectives of pharmacogenomics. Genetic variability, ranging from single nucleotide polymorphisms (SNPs) to copy number variations (CNVs), significantly impacts drug metabolism, efficacy, and adverse reactions. Methods such as genomic sequencing, bioinformatics, and statistical analyses enable the identification of genetic variants associated with drug response phenotypes. Clinical applications span oncology, cardiology, psychiatry, and infectious diseases, enhancing treatment precision and patient outcomes. Challenges include ethical considerations, regulatory complexities, and the need for robust evidence of clinical utility. Future directions encompass technological advancements, precision medicine initiatives, and artificial intelligence applications to further integrate pharmacogenomics into clinical practice. Embracing diverse populations and enhancing public awareness are crucial for equitable implementation. Pharmacogenomics stands poised to revolutionize healthcare, optimizing therapeutic efficacy while minimizing adverse effects through tailored drug therapies.