Oral anticoagulant therapy (OAT) based on vitamin K antagonists (VKAs; coumarin derivatives) is the current mainstay for the prevention and long-term treatment of a variety of thromboembolic disorders. Care of patients on OAT is challenging due to considerable variability in the response to a particular dose. This has been attributed to environmental, demographic, clinical and genetic variables. Individualized responses represent a major clinical challenge because patients may experience adverse health outcomes from bleeding or thrombosis as a result of over- or under-coagulation, respectively. Growing evidence indicates that up to 60% of the individual pharmacological response to coumarins might be due to genetic variables and affected by polymorphisms in the genes encoding two enzymes, namely, vitamin K epoxide reductase (VKOR) and cytochrome P450 CYP2C9. Genetic testing has been proposed as a useful tool for allowing prediction of the dose response during initial anticoagulation therapy, to assess variability in dose maintenance and to identify warfarin 'resistance'. However, genetic testing is not a panacea. Limitations include the optimal composition of test panels, still largely unknown, information concerning inter-individual variability, lack of analytical and quality specifications, lack of comprehensive outcome analyses to enable assessment of cost-effectiveness, lack of universal agreement related to reliable dosing algorithms and other ethical and social issues. The aim of this article is to provide a comprehensive overview of our current understanding of the pharmacogenetics of VKAs, as well as assessing potential advantages and limitations. Although it might be premature to recommend routine genetic testing, the future development and clinical validation of simple but comprehensive algorithms integrating the most informative gene polymorphisms (VKORC1 and CYP2C9) with some demographic information (age, race, body mass index) and clinical variables (comorbidities, drugs interference), and standardized dietary intake of vitamin K may provide a valuable tool in the care of patients on OAT with conventional VKAs. However, the ongoing development of new anticoagulant drugs targeting thrombin and factor X will introduce a paradigm shift in long-term anticoagulation therapy, so that consideration could be given to demise pharmacogenetics testing for VKAs.