The narrow therapeutic index, the large interindividual variability, and the severity of adverse drug reactions connected with vitamin K antagonists, together with their ample use in medical therapy, have prompted the search for strategies to better assist doctors in the choice of the safest and most effective dose of these drugs. The molecular mechanism by which oral anticoagulants exert their effect is an interference with the bioactivation of vitamin K. This mechanism is therefore the subject of numerous pharmacogenetic studies, aimed at finding the relationship between genetic variants influencing the metabolism or action of the drug and therapeutic outcomes. However, genes involved in the metabolism or action of vitamin K antagonists are many, and the role of some of them has not yet been fully understood. In this review we present and discuss current knowledge about the relationship between genotypes and the development of adverse drug reactions, focusing on gene variants that appear to influence dosing and clinical endpoints, and aiming at clarifying the usefulness of pharmacogenetic approaches as applied to this treatment.