Venous thromboembolism (VTE) remains a significant threat to public health despite the availability of effective and safe prophylactic measures and treatments. Guidelines based on randomized clinical trials are available to improve the management of thromboembolic disease. However, gaps exist between recommendations and clinical practice, and many patients are unnecessarily exposed to the risk of a deep vein thrombosis or potentially fatal pulmonary embolism. Barriers responsible for poor compliance with current antithrombotic guidelines include lack of familiarity with recommendations, overestimation of bleeding risk, underestimation of thrombotic risk, and logistical limitations of health care management systems. Improving compliance is a complex task, but successful initiatives rest upon improving thrombotic risk-assessment methods and facilitating appropriate prescribing of prophylaxis. Multifaceted, interdisciplinary strategies involving risk-assessment models, electronic reminders, and audit and feedback show the most potential to improve compliance with guidelines.