Following the landmark study by Barritt and Jordan in 1960, in which patients with venous thromboembolism (VTE) were randomized to no treatment or a combination of heparin and warfarin, antithrombotic therapy for this disease became widely accepted. This study was stopped prematurely because half of the non-treated patients had recurrent pulmonary embolism (PE), or died. It was subsequently found that after a VTE, patients given warfarin alone had a 3–4-fold higher incidence of recurrent VTE than patients given both heparin and warfarin. Since the 1990s, standard therapy for VTE has comprised an initial 5–7-day course of parenteral anticoagulant plus warfarin continued for at least 3 months. The first breakthrough was the introduction low molecular weight heparin (LMWH), which by its virtue of a fixed dose regimen given subcutaneously, allowed out of hospital treatment. The second breakthrough concerns the development of several orally active small molecules, which have been evaluated in the treatment of VTE, including a direct thrombin inhibitor and direct Factor Xa inhibitors. Other novel oral agents are also in development for VTE treatment, as well as a long-acting, reversible parenteral agent. Although the DTI ximelagatran, the first oral agent to be introduced since warfarin was withdrawn from the market in Europe because of hepatotoxicity, evidence from clinical trial evaluating other single target-specific oral agents in the treatment of VTE is convincing. It is therefore likely that use of heparin/warfarin in the treatment and secondary prevention of VTE will decrease now that these novel oral agents have been introduced for these indications. The first study in VTE with dabigatran was published in December 2009. The last large trial with edoxaban has been published in 2013. The clinical evidence from all these studies will be reviewed as well as what will be next.