The influence of genetic variations on drug efficacy has become an area of growing interest in the treatment of gastrointestinal (GI) disorders, particularly gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPIs), the cornerstone of GERD management, are metabolized by the cytochrome P450 enzyme CYP2C19, whose activity is highly variable due to genetic polymorphisms. Patients with CYP2C19 loss-of-function alleles (poor metabolizers) exhibit prolonged PPI exposure, leading to enhanced acid suppression, while those with gain-of-function alleles (ultra-rapid metabolizers) may experience suboptimal therapeutic effects. This variability in drug metabolism highlights the importance of personalized treatment approaches in GERD. Pharmacogenomic testing provides a novel and clinically relevant tool for identifying these genetic variants, allowing for tailored PPI dosing to maximize efficacy and minimize adverse effects, such as increased risks of Clostridium difficile infection or nutrient malabsorption associated with long-term PPI use. Recent clinical trials and observational studies underscore the benefits of incorporating pharmacogenomic testing into routine practice, where it has shown improved patient outcomes and medication adherence. Future research should focus on expanding pharmacogenomic testing to include other GI disorders and medications while addressing implementation barriers, including cost-effectiveness and clinician education. Integrating pharmacogenomics into clinical practice offers a promising pathway to personalized GI care, optimizing drug response, and enhancing therapeutic outcomes for patients with GERD.