The novel oral anticoagulants (NOACs) represent a major advance in the treatment of patients with nonvalvular atrial fibrillation and venous thromboembolism (VTE). They have several advantages over vitamin-K antagonists such as warfarin, including more predictable pharmacokinetics and improved safety, particularly with fatal bleeding and intracranial hemorrhage. However, several issues remain surrounding the use of NOACs in certain subpopulations and with the approach to reversal. The periprocedural management of anticoagulation with these relatively new agents can also present several challenges. This article reviews the basic pharmacology, efficacy, and safety of these drugs. Several populations at higher risk for complications with use of NOACs are discussed, including those undergoing procedures. Finally, several target-specific reversal agents have either received FDA approval or likely will be approved in the near future; these agents and their roles in the approach to anticoagulation reversal will also be discussed.