Anticoagulant drugs antagonize coagulation and are used to prevent or cure (recurrent) venous thromboembolism (VTE). Drugs to prevent clotting have been used for more than a century, and, nowadays, physicians possess a broad panel of multiple anticoagulants to meet the individual needs of a patient. Within this review, we aimed to revise the history of the different anticoagulants that are currently prescribed in the clinic. In addition, we compared their pharmacological properties, medical indications, and the difficulties in implementing new anticoagulants in vulnerable patient populations. Since the introduction of unfractionated heparin in the 1930s, major advances in the mechanistic understanding and the medical use of anticoagulants have allowed for significant improvements to treat VTE patients. However, a new generation of anticoagulants is currently being tested in clinical trials, with the goal of further optimizing medical care.