Atherothrombosis is a progressive and generalized pathologic process that affects the vascular system. Clinical manifestations of atherothrombosis depend on the affected vascular bed and include acute coronary syndromes, stroke, and peripheral arterial disease. Ischemia associated with atherothrombosis is highly prevalent, affecting millions of people each year. Many patients experience multiple ischemic events within the first year of an initial event. The mainstay for prevention includes risk factor management through lifestyle modification and treatment of underlying disease. Guidelines have been published for secondary prevention of atherothrombosis-related cardiovascular disease, including use of various long-term pharmacotherapies, such as antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors. Implementation of effective treatment strategies requires an awareness of the guidelines by physicians to ensure that both acute therapy and long-term management are addressed. This review is based on treatment guidelines and selected peer-reviewed publications identified through a MEDLINE and PubMed literature search, primarily from January 1996 to December 2006, that relate to clinical trials of antiplatelet therapy in patients with atherothrombotic disease. Secondary prevention strategies for patients with atherothrombosis are discussed, highlighting current guideline recommendations and programs designed to encourage a continuum of care from the acute to the ambulatory setting.