The paradigm of inherited thrombophilia as a cause of unprovoked venous thrombosis among young people and associated with a high clinical penetrance among members of the same kindred is challenged by many diagnosed cases not fitting this paradigm, although inherited thrombophilia is still the most likely diagnosis in most cases. However, all patients with venous thromboembolism are potential candidates for screening, regardless of the age at which the event occurs, the circumstances of thrombosis, and the severity of the clinical manifestations. A possible exclusion criterion is the contemporary presence of a high-risk disease for thrombosis such as cancer, since in such situations the presence of thrombophilic polymorphisms associated with a moderate risk for venous thromboembolism is not considered a significant additive risk factor. Potential candidates for screening are also women who have suffered from complications, other than venous thromboembolism, of a pregnancy. The inclusion of a large number of individuals with venous thromboembolism (or obstetric complications) in a diagnostic panel for inherited thrombophilia needs to be counterbalanced by a stringent selection of the laboratory tests. Screening should be limited to those traits that are more frequent or carry a higher thrombotic risk. A first-line diagnostic panel should include antithrombinheparin cofactor assay (functional amidolytic method), protein C assay (functional clotting or amidolytic method), and protein S assay (total and free fraction, measured by immunological methods). Analysis of DNA should include the search for factor V Leiden and the prothrombin G20210A. Genotyping for the C677T polymorphism in the methylenetetrahydrofolate reductase gene is quite meaningless, while homocysteine measurement is recommended. With the use of this panel, at least one third of the patients with venous thromboembolism can be diagnosed as carrying inherited thrombophilia; homocysteine measurement allows identification of at least a further 10% of patients with thrombophilia, achieving an overall diagnostic yield of more than 40%.