Although significant progress has been made over the past 25 years in preventing thromboembolic disease in patients undergoing total hip and total knee arthroplasty, important questions remain unanswered. Few would debate the need to seek a balance between maximal antithrombotic efficacy and minimal bleeding in choosing a thromboprophylactic strategy, but there is less agreement as to how efficacy should be defined, and whether efficacy and safety (however each is defined) are intrinsic to the thromboprophylactic agent chosen or depend as well on exogenous factors, ranging from the timing of drug administration to surgical technique. Differences between recent guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP) illustrate these unanswered questions. The AAOS guidelines focus solely on preventing symptomatic pulmonary embolism and ignores the importance of other acute and chronic manifestations of venous thromboembolic disease. The ACCP, on the other hand, does consider these other manifestations of venous thromboembolic disease, and thus reaches very different conclusions about what constitutes effective thromboprophylaxis. Despite these questions and uncertainties, there are fundamental truths: (1) venous thromboembolism (VTE) is a known and serious complication of total joint arthroplasty, and (2) evidence-based thromboprophylaxis works. Gaps between guideline-recommended and actual orthopedic practice must be reduced.