Vitamin K Antagonists (VKAs) are widely used in clinical practice and nearly 1% of the entire population receives oral anticoagulation at least once in life. However, the rate of prescription of anticoagulation is low, compared to what it should be. No more than 50-60% of patients affected by atrial fibrillation (AF) receive anticoagulation. In the setting of AF, VKAs are safe and effective when properly managed, reducing stroke and systemic embolism by more than 60%. VKAs safety and effectiveness are closely related to the quality of anticoagulation (e.g. time in therapeutic range), and anticoagulation clinics offer the best management of anticoagulant therapy. However, a sizeable proportion of patients are managed elsewhere. In clinical practice, in the setting of AF, a low prescription rate of VKAs is frequently observed and this is due also to difficulties in managing laboratory monitoring and drug dose adjustment. The suboptimal management of therapy with VKAs leads to a lesser efficacy than that reported in clinical trials, and to an increase in adverse reactions. VKAs still remain the first and only available therapy for a number of diseases (e.g. valvular atrial fibrillation and mechanical prosthetic heart valves). Now, since approval of the new oral anticoagulants (NOAs), the choice of anticoagulant therapy in definite settings, such as stroke prevention in non-valvular atrial fibrillation (SPAF) or treatment of venous thromboembolism, has surely become more intriguing but also more problematic. In light of these new therapeutic options, we reviewed VKAs therapy, in the setting of atrial fibrillation, focusing on VKAs impact in real life. We analyzed the data about efficacy and safety of warfarin at three levels: clinical trial and real life, outside and inside anticoagulation clinics.