Heparin has an established place in the treatment of venous thrombosis. It is also effective in syndromes of arterial occlusion, such as unstable angina, although its benefit: risk ratio when combined with thrombolytic drugs in the treatment of myocardial infarction remains open to debate. Specific thrombin inhibitors have several theoretical advantages over heparin. However, they have failed to realize their promise in phase III trials, perhaps because of inadequacies in trial design. Our understanding of protease-activated receptors, such as that for thrombin, is modest and the comparative advantages of receptor antagonism versus specific thrombin inhibition are unknown. Increasing usage of low molecular weight heparins and glycoprotein IIb/IIIa antagonists provide a changing context for evaluation of these drugs. Problems in phase III clinical trials might be minimized by placing greater emphasis on dose finding in phase II.