Thrombocytopenia—a pathological reduction in platelet count—has five major explanations: decreased platelet production, hemodilution (usually postoperative), sequestration (hypersplenism), increased platelet consumption, and increased platelet destruction. Consumptive thrombocytopenic disorders include thrombin-mediated (disseminated intravascular coagulation), septicemia, and thrombotic microangiopathy (thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome), whereas platelet destruction indicates increased platelet clearance due to platelet-reactive autoantibodies, alloantibodies, or drug-dependent antibodies. The adverse drug reaction, heparin-induced thrombocytopenia, combines these concepts of platelet consumption and destruction, as the pathogenic antibodies bind to platelet factor 4/heparin complexes on platelet surfaces, but results in increased platelet activation, hypercoagulability, and a prothrombotic state. When faced with a thrombocytopenic patient, the clinician must ask: what is the probable cause of the patient’s thrombocytopenia? The answer to that question indicates whether the patient’s major risk is bleeding, thrombosis, or increased mortality (due to multiorgan dysfunction), and what the appropriate therapies might be.