The relative efficacy and safety of new oral anticoagulants (NOAC) have been consistent across a wide range of patients in clinical trials. On the one hand, they have offered new therapeutic options for stroke prevention in patients with atrial fibrillation (AF) and patients do like the experience of no need of frequent blood draws. On the other hand, their expensive prices, different formulary plans from different insurance companies, lack of antidote, and no method of monitoring the therapy are some of the challenges on their use in clinical practice. This narrative review aims to help clinicians understand these new oral anticoagulants better and choose them wisely according to their indications. In addition, other issues related to the use of NOAC, such as cost and methods of reversing their effects in hemorrhagic conditions, are also discussed.