Over the past two decades, advances in the prevention and treatment of coronary artery disease, e.g., coronary angioplasty and coronary thrombolysis, have been coupled with the need for improved antithrombotic therapy to prevent acute, life-threatening thrombotic complications. Concurrently, studies on the pathophysiologic mechanisms for the arterial thrombotic process have demonstrated a central, mediating role for thrombin. Brought forward from its identification in the late 19th century, the leech protein hirudin emerged as a model for recombinant DNA engineering and ‘protein-mimetic’ drug design. Recombinant hirudin (r-hirudin) and Hirulog are the resulting drug candidates which, as direct thrombin inhibitors, offer several potential advances in the management of acute thrombotic disorders. Clinical trials of these drug candidates have already provided evidence for clinical activity and tolerability in thromboembolic disease. Definitive evidence for efficacy is currently sought in large, controlled studies in the settings of coronary angioplasty, coronary thrombolysis and unstable angina.