Nurse practitioners (NPs) frequently treat adults with atrial fibrillation. With new oral antithrombotic agents available, NPs need to be knowledgeable of treatment options to prevent stroke and systemic emboli. This article reviews the latest American College of Cardiology Foundation/American Heart Association guideline on the management of atrial fibrillation. Emphasis is placed on the changing landscape of pharmacological agents. Use of guideline-directed medical therapy will ultimately improve patients’ quality of life and prevent stroke and premature death.