Recent reports of catheter thrombosis among patients undergoing percutaneous coronary intervention (PCI) have had a significant impact on the development of new antithrombotic therapies. The overall incidence of this complication is unknown, mainly because of underreporting in contemporary clinical trials of coronary intervention. The etiology and pathophysiology of catheter thrombosis is also poorly understood. Introduction of a catheter or guidewire may not provoke the intense thrombotic response that follows angioplasty or stenting, but factors such as catheter materials and device size, equipment surface properties, flow conditions, procedural time and complexity, as well as the antiplatelet and anticoagulant drugs administered during the procedure influence the likelihood, rate and clinical impact of thrombosis. The crucial role of cellular interactions involving tissue-factor bearing cells and platelets in the process of thrombosis also needs to be critically explored when considering blood contact with an exogenous material. Focusing on the inherently prothrombotic environment of percutaneous coronary intervention, we review the physiologic underpinnings of catheter and guidewire thrombosis, and explore the effect of antithrombotic drugs at the interface between blood and material surfaces. We also propose a clinical classification for the diagnosis and investigation of catheter thrombosis in clinical trials of anticoagulant therapy and PCI.