Hypertension is a major cause of cardiovascular diseases, with significant morbidity and mortality worldwide. While many effective antihypertensive drugs are on the market, patients respond variably to these drugs because of genetic variations in drug metabolism. Pharmacogenomics-the analysis of how genetic variation affects drug response-provides a tailored method for optimizing antihypertensive treatment. This review examines the impact of polymorphisms in the CYP2D6 and CYP3A5 enzymes on the metabolism of commonly prescribed beta-blockers and calcium channel blockers. Polymorphisms in CYP2D6 can have a dramatic impact on the degradation of beta-blockers, influencing drug clearance and leading to variable therapeutic effects. Poor metabolizers may develop higher drug levels, increasing the potential for side effects such as bradycardia and hypotension. Conversely, ultra-rapid metabolizers can clear the drug too rapidly, decreasing its efficacy. Likewise, CYP3A5 polymorphisms influence the metabolism of calcium channel blockers. Those who express CYP3A5 metabolize the drugs more rapidly and potentially need greater doses, whereas non-expressers metabolize them more slowly, raising the potential for drug build-up and toxicity. Pharmacogenomic testing incorporated into everyday practice can allow for individualized antihypertensive treatment according to an individual's genotype. This precision strategy increases treatment efficiency, reduces side effects, and enhances patient compliance. A transformation from a general to a personalized treatment paradigm by pharmacogenomics has the potential to transform the management of hypertension and enhance cardiovascular outcomes.