Thromboembolic disease remains one of the most devastating and potentially lethal complications after elective total knee replacement (TKR) surgery. Studies have shown that 40-85% of patients undergoing TKR will develop venographically confirmed deep vein thrombosis (DVT) if they are not given any type of post-operative thromboprophylaxis and approximately 0.1 to 1.7% will suffer fatal pulmonary embolism (PE). Consequently, there is a general consensus that patients undergoing elective TKR require adequate antithrombotic prophylaxis. The following article reviews current evidence regarding chemical thromboprophylaxis after total knee replacement. Clinical guidelines as described by the American Academy of Orthopaedic Surgeons (AAOS), the American College of Chest Physicians (ACCP) and the UK's National Institute for Health and Clinical Excellence (NICE) are summarized along with the differences between the recommendations. The results of the new oral anticoagulants are reviewed as well as the most recent developments in the search for the most effective venous thromboembolism (VTE) prophylaxis after TKR surgery.