Direct oral anticoagulants (DOACs) are novel, direct acting drugs that are selective for either thrombin or activated factor X. Due to their obvious benefits for patients (broader therapeutic window, are not routinely monitored etc.), they are increasingly used as an alternative to vitamin K antagonists. One of the major indications for the use of DOACs is the stroke prevention in patients with atrial fibrillation (AF). Although, the DOAC use becomes extensive in the clinical area especially cardiology, many drug drug interactions occur when DOACs are used with other drugs. Also, the safety profile of DOACs is still to be investigated. Animal models can be used to investigate the drug drug interactions and safety of DOACs under standart laboratory conditions. Unfortunately, there is not sufficient data that investigates the drug drug interactions and safety of DOACs in animal models. The focus of this review will be the availability, use and development of animal models to assess drug drug interactions and safety profile of DOACs.