Since 1965, when antithrombin deficiency was identified as the first congenital defect of hemostasis able to increase the risk of thrombosis, we have assisted in a substantial evolution of thrombophilia. From the original monogenic view, it has been demonstrated that thrombosis is a polygenic and complex disorder that involves potentially hundreds of polymorphisms and rare mutations, as well as multiple acquired and triggering factors. From the enthusiasm of searching prothrombotic polymorphisms that might contribute to the risk of each individual to have a thrombotic episode, to the frustration of considering that thrombophilic tests might have no clinical relevance. Also the methods used in thrombophilic analysis have significantly changed from original simple analysis to recent and complex technological approaches. It is time to analyze carefully, without any pressure, the real state of the art and to moderate the conclusions, separating clinical use and research of inherited thrombophilic conditions.