Direct oral anticoagulants (DOACs) are novel direct-acting medications that are selective for either thrombin or activated factor X. Due to their obvious benefits for patients (fewer interactions, broader therapeutic window, etc.), they are increasingly used as an alternative to warfarin, phenprocoumon, or acenocoumarol. One of the major indications for use of DOACs is stroke prevention in patients with atrial fibrillation (AF). However, interactions still exist, especially in combination with antiarrhythmic drugs (AADs), which are frequently given to AF patients for rhythm or rate control. These interactions are due to the cytochrome P450 system and the P-glycoprotein (permeability glycoprotein or multidrug resistance protein) transport system. For some combinations, dose reduction of the DOAC is recommended and in some cases contraindications exist. In addition, impairment in renal and hepatic function plays an important role in this context. However, compared with pure interactions where data are quite convincing, the latter topic has been studied only rudimentarily. This review summarizes the literature on the safety and interactions of AADs when used with DOACs [dabigatran (a direct inhibitor of factor IIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa)] and the impact of renal and hepatic impairment.