For decades, unfractionated heparin (UFH) was the most widely used parenteral anticoagulant in a variety of clinical scenarios requiring rapid and reversible anticoagulation. The shortcomings of UFH include a high inter-individual variability and the occurrence of heparin induced thrombocytopenia with the potential for serious thromboembolic complications. These shortcomings prompted the successful clinical development of low molecular weight heparins (LMWH) and indirect factor Xa inhibitors such as fondaparinux. LMWH and fondaparinux demonstrated superiority in many clinical scenarios including acute coronary syndromes (ACS). However the long half-life and the lack of a specific antidote still require the usage of UFH in clinical situations where a rapid reversibility of the anticoagulation is required. Especially in ACS patients undergoing PCI, a direct parenteral inhibition of thrombin with the direct thrombin inhibitor (DTI) bivalirudin proved to be an alternative anticoagulant strategy. This has set the stage for the clinical development of other parenteral DTIs. The reduction in clinical ischemic events that were achieved with indirect factor Xa inhibitors in patients with ACS facilitated the clinical development of the first parenteral direct factor Xa inhibitor, otamixaban which is currently investigated in a phase III clinical trial in patients with ACS undergoing PCI. This article discusses novel parenteral factor Xa and thrombin inhibitors currently under clinical investigation including aptamers, a new class of drugs that allows the parallel development of the combination of active drug and reversal agent, which is facilitated by the DNA or RNA structure of which aptamers are composed of.