Compared with warfarin, the direct-acting oral anticoagulants (DOAC) have fewer pharmacokinetic drug interactions. However, significant drug interactions do exist with documented changes in DOAC concentrations, which can exceed 100%. Unlike warfarin, DOACs have no validated surrogate test to monitor the intensity of anticoagulation. However, several analyses of major outcomes trials with DOACs have demonstrated that serum concentrations do affect both the thrombotic benefits and the hemorrhagic risks of these agents. This paper reviews the known significant pharmacokinetic interactions with DOACs and includes considerations for their use in the presence of interacting medications.