Millions of individuals in the United States require long-term treatment with an oral anticoagulant. For decades, vitamin K antagonists were the only oral option available; however, they have a number of well-known limitations. Introduction of the direct oral anticoagulants (DOACs) has long been considered a major therapeutic advance, largely because they lack the need for therapeutic monitoring. Despite this, DOACs, like vitamin K antagonists, can still cause major and clinically relevant nonmajor bleeding, even when used appropriately. Drug-drug interactions (DDIs) involving the DOACs represent an important contributor to increased bleeding risk. Awareness of these DDIs and how best to address them is of critical importance in optimizing management while mitigating bleeding risk. This review provides an overview of DOAC metabolism, the most common drugs likely to contribute to DOAC DDIs, their underlying mechanisms, and how best to address them.