Antithrombotic therapy has a pivotal role in optimizing outcomes in patients undergoing percutaneous coronary intervention (PCI). In particular, anticoagulant therapy is mandatory during PCI. Thrombin represents one of the most potent platelet activators and its levels are known to be particularly high in the initial phase of an acute coronary syndrome (ACS). Therefore, the use of parenteral anticoagulation plays a fundamental role in the reduction of thrombus burden and flow obstruction at the site of the culprit lesion in ACS and of atherothrombotic complications associated to PCI, representing a key antithrombotic strategy to be used during PCI for both ACS and stable patients. Anticoagulant drugs available for parenteral use during PCI are indirect thrombin inhibitors (unfractionated heparin and low-molecular-weight heparin) and the direct thrombin inhibitors bivalirudin and argatroban. These agents have different mechanisms of action, pharmacological characteristics, and effects on platelet function, as well as different clinical profiles. Over the past four decades, there has been an evolution in the approach to antithrombotic therapy used in patients undergoing PCI. This may be attributed to significant improvement in stent technologies, the development of new antithrombotic drugs, and the understanding of the prognostic implications associated with bleeding, which led to investigate antithrombotic strategies that mitigate bleeding without any trade-off in thrombotic events. This chapter is aimed to review currently available parenteral anticoagulant therapies for patients undergoing PCI, with a particular focus on patients with high bleeding risk.