Aspirin, heparin and the coumarins are the classical anti-thrombotic agents. They represent the platform upon which newer drugs holding the promise of greater efficacy and less toxicity are being developed. Even as such newer drugs arrive into clinical practice, the older agents remain remarkable for their decades-long pre-eminence. All derive from natural sources, and none from a search for therapeutic anti-thrombotic agents; they have saved countless lives but also served as essential probes into basic mechanisms of thrombosis. Testament to their clinical importance is that these agents are the only drugs profiled on a regular basis in special scientific statements by the American Heart Association/American College of Cardiology and by the American College of Chest Physicians. This chapter reviews their biology, uses and limitations.