Hypercoagulability can be defined as the tendency to have thrombosis as a result of certain inherited and/or acquired molecular defects. Clinical manifestations of hypercoagulability can be devastating and even lethal. In the past 20 years, the origin of most of these diverse hypercoagulability syndromes has been elucidated. Currently, hypercoagulability disorders can be correctly diagnosed in approximately 80% to 90% of patients. Defining the cause of hypercoagulability may determine the type and duration of treatment for the associated thrombosis. The discovery of an occult carcinoma allows for the possibility of early and possibly curative treatment. Finding a genetic defect in coagulation allows for testing of asymptomatic family members as well. The purpose of this review is to provide internists with a logical approach to the identification and treatment of hypercoagulability syndromes.