Although highly effective, warfarin use is complicated by its unpredictable narrow therapeutic window, genetic heterogeneity in pharmacokinetic response, numerous food and drug interactions, and the need for regular international normalized ratio (INR) monitoring. Currently, several novel oral anticoagulant (NOAC) drugs (dabigatran, rivaroxaban, apixaban) are available on the market as alternatives to warfarin. These agents all feature more predictable pharmacodynamic and pharmacokinetic properties than warfarin. Additionally, the NOACs do not require routine monitoring of coagulation parameters, and have a relatively lower potential for interactions with drug, herb, and dietary constituents, which enhances the convenience of management for both patients and health professionals alike. However, there are other considerations regarding the use of NOACs that must be taken into account during management of therapy. In contrast to warfarin, most NOACs need dosage adjustments in renal impairment and are contraindicated in severe liver impairment, and there are no specific antidotes for treating NOAC-related over-anticoagulation. The more frequent dosing needed for NOACs may reduce adherence, especially in elderly patients with polypharmacy. Furthermore, NOACs, especially dabigatran, are not as well tolerated as warfarin in patients with gastrointestinal diseases. Overall, the availability of the NOACs has expanded the treatment armamentarium, but they are not without risk. Given the limited experience with the NOACs, their limited range of indications, and their cost, the characteristics of each anticoagulant must be carefully considered to carefully select the agent that will provide the optimal risk/benefit profile in the individual patient.