Venous thromboembolism (VTE) susceptibility genes are widely diffuse in the general population, but clinical penetrance of genotypes is incomplete and has variable expressivity. Therefore, the indiscriminate search for carriers is of doubtful utility and potentially detrimental for screened individuals. A targeted screening in kindreds in which VTE already occurred can be more fruitful in identifying individuals sharing with the proband one or more known susceptibility genes (possibly cosegregating with other ones still unknown). Clinical penetrance is variable, and is higher in the relatively rare deficiencies of antithrombin (AT), protein C (PC), or protein S (PS), and lower in the presence of the common polymorphisms factor V Leiden and prothrombin G20210A. Women with inherited thrombophilia should be warned about the thrombotic risk associated with the use of oral contraceptives or hormonal replacement treatment. Moreover, prophylaxis during puerperium and surgery or after trauma is warranted. The absolute risk associated with such situations is low but not negligible in the presence of deficiencies of AT, PC, or PS, homozygous conditions, and carriership of multiple defects. In such cases primary prophylaxis should be applied also during pregnancy and in general should be more stringent; moreover, in these patients the option for indefinite duration of secondary anticoagulant prophylaxis after VTE should be considered because of the relevant risk of recurrent VTE. In all cases, a careful balance of benefits and risks associated with prophylactic measures should be achieved, and patient preferences should be considered.