The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1% during 3-month follow-up. The negative predictive value (NPV) during 3 months of follow-up is 98.1 to 99% after a normal venogram, 97 to 98% after a normal compression ultrasonography (CUS), and > 99% after serial CUS testing. Serial CUS testing is safe but 100 CUS must be repeated to find one or two CUS positive for deep vein thrombosis (DVT), which is not cost-effective and indicates the need to improve the diagnostic workup of DVT by the use of clinical score assessment and D-dimer testing. The NPV varies from 97.6 to 99.4% for low clinical score followed by a negative SimpiRED test, indicating the need for a first CUS. The NPV is 98.4 to 99.3% for a normal rapid enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer test result (< 500 ng/mL) irrespective of clinical score. The NPV is more than 99% for a negative CUS followed by either a negative SimpiRED test or an ELISA VIDAS test result of < 1000 ng/mL without the need to repeat a second CUS within 1 week. The sequential use of a sensitive, rapid ELISA D-dimer and clinical score assessment will safely reduce the need for CUS testing by 40 to 60%. Large prospective outcome studies demonstrate that with one negative examination with complete duplex color ultrasonography (CCUS) of the proximal and distal veins of the affected leg with suspected DVT, it is safe to withhold anticoagulant treatment, with a negative predictive value of 99.5%. This may indicates that CCUS is equal to serial CUS or the combined use of clinical score, D-dimer testing, and CUS. Pulmonary angiography is the gold standard for segmental pulmonary embolism (PE) but not for subsegmental PE. A normal perfusion lung scan and a normal rapid ELISA VIDAS D-dimer test safely excludes PE. Helical spiral computed tomography (CT) detects all clinically relevant PE and a large number of alternative diagnoses in symptomatic patients with suspected PE and can replace both the ventilation perfusion scan and pulmonary angiography to safely rule in PE and to rule out PE with an NPV of > 99%. The combination of clinical assessment, a rapid ELISA VIDAS D-dimer, followed by CUS will reduce the need for helical spiral CT by 40 to 50%.