Patients who are at risk for venous thromboembolism may require prophylaxis with oral anticoagulant agents. In South Africa, available oral anticoagulant agents include warfarin and the new oral anticoagulants (NOACs): dabigatran, rivaroxaban and apixaban. Whilst NOAC agents have benefits over warfarin therapy in terms of therapeutic window, onset of action and monitoring requirements, multiple clinical factors need to be considered when selecting an anticoagulant agent for a patient.This review article explores clinical considerations for the rational use of oral anticoagulants and includes discussions on bleeding events, risk of drug interactions, safety in renal and hepatic impairment, and safety and efficacy in obesity.Warfarin and NOACs are subject to potential drug-drug interactions. It is important to consider the patient's concomitant medication and the clinical significance of interactions. The safety of NOACs in kidney and liver disease has not been extensively explored; thus, the use of NOACs is often limited to patients with mild-moderate cases of these diseases. In more severe cases of disease, warfarin remains the drug of choice, subject to close international normalised ratio (INR) monitoring.The safety of NOACs in obesity has not been adequately investigated. Further studies are required to inform anticoagulant recommendations in obese patients. In severely obese patients, warfarin, with close INR monitoring, remains the drug of choice.When comparing warfarin and the NOACs, it is evident that there is no "ideal" agent which is preferable in all clinical settings. Rational use of anticoagulant therapy requires consideration of patient-specific factors. The information provided in this review aims to guide pharmacists when assessing the rational use of anticoagulant therapy.