Patients undergoing major orthopedic surgery are at high venous thromboembolism (VTE) risk, with morbid and potentially fatal consequences. Anticoagulant VTE prophylaxis reduces rates of postoperative deep vein thrombosis by up to 60% to 70% in these patients. Therefore, pharmacological prophylaxis with low-molecular-weight heparins (LMWHs), vitamin K antagonists, or fondaparinux is recommended by current guidelines. However, there remains an ongoing debate regarding when to initiate and the optimal duration for prophylaxis. Here, we discuss the mechanisms underlying thrombus formation in patients undergoing major orthopedic surgery, and we review the current literature on the benefit-to-risk ratio associated with preoperative and postoperative initiation of thromboprophylaxis and also the benefit-to-risk ratio in cases of neuraxial anesthesia. We also discuss the duration of postoperative VTE risk following major orthopedic surgery and assess the ''critical thrombosis period'' when prophylaxis should be provided. Current literature reflects the need to balance the improved efficacy of initiating prophylaxis close to the surgery with increased risk of perioperative bleeding. Evidence from pathology, epidemiology, and clinical studies suggests the risk period for VTE begins at surgery and extends well beyond hospitalization-a crucial issue when considering how long to give prophylaxis-and, in the case of total hip arthroplasty, for at least 3 months after surgery. Literature supports the greater use of ''just-in-time'' thromboprophylaxis initiation and after-discharge continuation of optimal prophylaxis in orthopedic surgery patients. Providing optimal thromboprophylaxis throughout the critical thrombosis period where a patient is at VTE risk will ensure the best reductions in VTE-related morbidity and mortality.