An adequate regimen for prophylaxis of venous thromboembolism (VTE) requires identification of reversible and irreversible risk factors. Recent data confirm that the greatest number of pulmonary emboli (PE) occur in non-surgical patients. VTE also develops in many surgical patients upon hospital discharge. These findings emphasize the need for adequate VTE prophylaxis in inflammatory diseases, acute medical illness, and other conditions, as well as the need to optimize anticoagulant regimens after surgery. Establishing VTE risk factors, identifying acquired or inherited thrombophylias and occult or previously undiagnosed malignancy will help design an adequate anticoagulant regimen as secondary VTE prophylaxis for surgical and other patients. Follow up measures should include D-dimer values, ultrasonographic assessment of residual venous thrombosis and echocardiographic parameters, along with other relevant clinical data to assess the risk of VTE reoccurrence. These procedures will ensure the optimal duration of individually tailored anticoagulant therapy, with special attention to comorbidities and tendency to hemorrhage.