Deep vein thrombosis (DVT) is a common disease. In a review published in 2013, we provided a comprehensive history of DVT management, with particular emphasis on treatments that were later introduced or abandoned. At that time, the history of direct oral anticoagulants was still emerging, and we chose not to delve into this topic at that point. Twelve years later, direct oral anticoagulants have become the standard of care for DVT treatment, not only revolutionizing management by simplifying therapy but also influencing the intensity and duration of anticoagulant treatment. This new historical review focuses on aspects of DVT treatment that were not covered previously, including the quest of the development of safer and more user-friendly alternatives to older anticoagulants, the evolving history of anticoagulant treatment duration and intensity, as well as how studies have influenced the American College of Chest Physicians guidelines. Although great successes have been achieved, this review will highlight that anticoagulation philosopher's stone has yet to be found, if ever found. Nevertheless, recent data on inhibitors of factor (F)XI/XIa might suggest that we are approaching closer to safer anticoagulants. Looking ahead, in the absence of possibility for a single universal treatment for DVT, the future of DVT treatment will probably lie both on the development of newer anticoagulants and on the development of artificial intelligence, which could offer individualized treatment.