BACKGROUND: In 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine. CONTENT: In this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants. These genetic variations have pharmacodynamic and pharmacokinetic effects and have been shown to explain differences in drug response such as lipid lowering, prevention of cardiovascular disease, and prevention of stroke, as well as incidence of adverse events such as musculoskeletal side effects and bleeding. Several groups have begun to implement pharmacogenetics testing as part of routine clinical care with the goal of improving health outcomes. Such strategies identify both patients at increased risk of adverse outcomes and alternative strategies to mitigate this risk as well as patients with "normal" genotypes, who, armed with this information, may have increased confidence and adherence to prescribed medications. While much is known about the genetic variants that underlie these effects, translation of this knowledge into clinical practice has been hampered by difficulty in implementing cost-effective, point-of-care tools to improve physician decision-making as well as a lack of data, as of yet, demonstrating the efficacy of using genetic information to improve health. SUMMARY: Many genetic variants that affect individual responses to drugs used in cardiovascular disease prevention and treatment have been described. Further study of these variants is needed before successful implementation into clinical practice.