Heparin-induced thrombocytopenia (HIT) creates an extreme thrombotic diathesis that requires emergent alternative anticoagulation. The discovery of the disorder, its complications and treatment principles, emanated from observational retrospective clinical case series. These established the need to urgently begin an alternative (non-heparin) anticoagulant even with isolated HIT, and to shun early warfarin use. Danaparoid emerged as a favored alternative anticoagulant, based on a large registry database and expert opinion. The direct thrombin inhibitors lepirudin and argatroban were approved for HIT by the US FDA based on prospective clinical trials that used historical controls; active controls were impossible because there were no established alternative agents, whilst placebos were not ethically acceptable. Postmarketing observational case series improved recommended dosing and other nuances for optimal use of these drugs. The only two attempts at randomized controlled trials have consisted of danaparoid versus dextran, which begun 25 years ago, and recently, desirudin versus argatroban. Both studies experienced very poor accrual. Currently, argatroban is the only FDA-approved agent on the market; however, bivalirudin and fondaparinux enjoy increasing use despite the absence of validated clinical trial data. Dabigatran, rivaroxaban, apixaban and other new anticoagulants will have future roles in disease prevention and treatment. HIT illustrates how major advances in understanding and therapy of a disease can advance rapidly even without major controlled trials, and gives testimony to the willingness of physicians to use agents perceived beneficial without trials or formal approvals. In an age emphasizing importance of the randomized prospective trial, HIT gives credence to the ever-present value of clinical case series and of insightful observations made by the prepared mind.