Our understanding of the pathophysiology of unstable angina (UA) and non-ST-segment elevation (NSTE) myocardial infarction (MI) [commonly referred to as NSTE acute coronary syndrome(s) (ACS)] has evolved considerably over the years, with atherothrombosis playing a pivotal role. This review discusses the molecular interactions in coronary thrombosis that may serve as therapeutic targets for more effective management of these syndromes. The purposes of this review are: 1) to discuss current understanding of the pathophysiology of NSTE ACS; 2) to describe recent studies with novel antithrombotic agents [e.g., low-molecular-weight heparin, thienopyridines, glycoprotein (GP) IIb-IIIa inhibitors] in patients with NSTE ACS; and 3) to highlight recommendations for management of patients with NSTE ACS in the recently updated American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines, including the appropriate use of antithrombotic therapies.