Acute coronary syndromes (ACS) are a common presentation of coronary artery disease, accounting for more than one million hospital admissions in the US annually. Owing to high rates of mortality and reinfarction, ACS represent a major public health concern. The following review discusses the pathogenesis of ACS and optimal approaches for the management of patients with ACS, with special focus on new antithrombotic strategies, including the direct thrombin inhibitor bivalirudin. Bivalirudin has several notable mechanistic advantages compared with unfractionated heparin, including activity against clot-bound thrombin, inhibition of thrombin-induced platelet activation, short plasma half-life in patients with normal or mildly impaired renal function (25 minutes), and linear pharmacokinetics less affected by plasma proteins and renal insufficiency. These properties provide a more predictable inhibition of coagulant activity than unfractionated heparin, with less degree of inter-patient variability in anticoagulation response. The findings from the several clinical trials assessing safety and efficacy of bivalirudin are analyzed in detail, including the recent randomized controlled Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Based on the results of the ACUITY trial, a newer streamlined strategy for the invasive treatment of moderate- and high-risk patients with ACS is discussed.