Venous thromboembolism (VTE) is an important cause of preventable morbidity and mortality in medically ill patients. Randomized controlled trials indicate that pharmacologic prophylaxis reduces deep venous thrombosis (relative risk [RR] = 0.46; 95% confidence interval [CI], 0.36-0.59) and pulmonary embolism (RR = 0.49; 95% CI, 0.33-0.72) with a nonsignificant trend toward more bleeding (RR = 1.36; 95% CI, 0.80-2.33]. Low-molecular-weight heparin (LMWH) and unfractionated heparin are equally efficacious in preventing deep venous thrombosis (RR = 0.85; 95% CI, 0.69-1.06) and pulmonary embolism (RR = 1.05; 95% CI, 0.47-2.38), but LMWH is associated with significantly less major bleeding (RR = 0.45; 95% CI, 0.23-0.85). LMWH is favored for VTE prophylaxis in critically ill patients. New VTE and bleeding risk stratification tools offer the potential to improve the risk-benefit ratio for VTE prophylaxis in medically ill patients. Intermittent pneumatic compression devices should be used for VTE prophylaxis in patients with contraindications to pharmacologic prophylaxis. Graduated compression stockings should be used with caution. VTE prevention in medically ill patients using extended-duration VTE prophylaxis and new oral anticoagulants warrant further investigation. VTE prophylaxis prescription and administration rates are suboptimal and warrant multidisciplinary performance improvement strategies.