Until recently, the confusing clinical profile of HIT and the widespread unavailability of reliable diagnostic assays have conspired to produce under-recognition-if not frank skepticism-of the clinical importance of HIT. However, during the 1990s, HIT has emerged as one of the major-if not the most important-immunohematologic problems in clinical medicine. The clinical and laboratory investigations summarized here have contributed to a greater understanding of the frequency, clinical spectrum, pathogenesis, laboratory diagnosis, and-potentially-the prevention of this important drug allergy. Further, the demonstration of increased platelet procoagulant activity and, thrombin generation in HIT, together with insights into the pathogenesis of a new clinicopathologic syndrome (venous limb gangrene), help explain how a disorder characterized by IgG-mediated platelet activation can lead to such diverse clinical sequelae as venous thrombosis, pulmonary embolism, disseminated intravascular coagulation, and venous limb gangrene. These studies should lead to improved treatment of HIT (new emphasis on suppression of thrombin generation, eg, hirudin and its analogs), future avoidance of HIT (preparation of low-molecular-weight heparins and heparinoids that are less immunogenic), and a greater understanding of the interaction between platelet activation and procoagulant/anticoagulant processes.