Blood clotting is a complex process that controls bleeding when tissues are injured. Unfortunately, this same process is capable of producing life-threatening thrombi in response to pathophysiological events. Blood clots may form in large and small vessels in response to triggers from disrupted vessel walls, inflammatory cells, cytokines, and other pathology. Platelet-rich clots can impair circulation to the myocardium and brain, leading to acute coronary syndromes and stroke. Erythrocyte-rich clots can embolize from the deep veins and threaten the lungs with pulmonary emboli. Microthrombi can block the circulation to tissues and organs in disseminated intravascular coagulation. An understanding of the pathogenesis of these various clotting syndromes directs effective intervention and preventive measures, minimizing the number of deaths by clot.