Atrial fibrillation is the most common cardiac arrhythmia in adults, affecting approximately 59.7 million people worldwide as of 2019—a 111% increase since 1990. Over the past 20 years, the prevalence of AF has risen by 33%, and it is projected to increase by more than 60% by 2050. Age plays a critical role in the factors that contribute to AF. Its prevalence is low (0.1%) in adults under 55 years old but rises to 5.9% in individuals aged 65 and older and 9.0% in those aged 80 and older. In this chapter, we provide a brief history of vitamin K antagonists and direct oral anticoagulants, both of which play a paramount role in atrial fibrillation. We also review the main differences between these two classes of anticoagulants. Furthermore, we aim to address the most common issues associated with DOACs use, particularly concerning patients with renal failure, obesity, and elderly or frail individuals. Lastly, we will discuss some remarks on randomized controlled trials and their limitations. The pivotal role of anticoagulation clinics is also highlighted here, underscoring the need for regular follow-up of both VKAs and DOACs.