Heparin-induced thrombocytopenia and thrombosis (HITT) is both life-threatening with a complex immune-mediated process and clinically challenging to diagnose and treat. What further complicates matters is that thrombocytopenia is a frequently encountered laboratory value but rarely results in clinical signs of HITT. Decades into its initial description, we have anticoagulants with a small therapeutic index and associated high cost. The diagnosis is sometimes equivocal given our current laboratory diagnostics, and can take days to confirm. Furthermore, prior studies that resulted in the approval of anticoagulants for the treatment of heparin-induced thrombocytopenia have been imperfectly designed. Further evaluations of patients with HITT could more adequately define these difficult issues.