Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia, and its prevalence is increasing, partly due to the progressive aging of the population. AF predisposes to thrombus formation in the atria and the atrial appendage through a complex interaction among local, systemic and hemodynamic factors, significantly increasing the risk for cerebral and systemic thromboembolic events. These complications have a major impact in terms of morbidity and mortality, and numerous therapeutic strategies have been proposed to reduce such risk. Systemic anticoagulation is the main strategy in the prevention of atrial and left atrial appendage thrombosis, and the advent of non-vitamin K antagonist oral anticoagulants (NOACs) has been a significant step forward, especially for safety, compared to warfarin. While prevention of atrial appendage thrombosis with NOACs has been widely explored, their role in the resolution of thrombi is less clear. The use of NOACs in this setting is largely unexplored, and some studies are underway to clarify their effectiveness. The objective of this paper is to review the literature on atrial and left atrial appendage thrombosis, describing pathophysiological mechanisms and current treatment strategies using NOACs.