Pharmacogenomics (PGx) is aimed at preventing or reducing adverse effects and treatment failures from medications, two highly prevalent outcomes of pharmacotherapy in older adults. Underrepresentation of older adults in clinical trials and phenoconversion from multicomplexity factors represent challenges in applying PGx in this population. Clinical decisions for which PGx shows promise despite these challenges include initial dosing decisions and more precise identification of older adults for whom the AGS Beers Criteria® recommendations are likely to be most applicable. Despite the complexities of integrating PGx data into clinical decision-making for older adults, emerging evidence shows potential for improved outcomes, especially where drug–drug–gene interactions are considered.