Much has been learned about thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT) and much remains a diagnostic and management challenge. While the pentad of thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic abnormalities characterize the clinical presentation of TTP, few patients present with all signs and symptoms. Worse yet, the pentad and its components are seen in other so-called thrombotic microangiopathies that demand different treatment approaches. HIT is another systemic disorder presenting with thrombocytopenia and/or thrombosis with potential devastating consequences whose diagnosis is difficult and management is still evolving. Highlights of the conditions and clinical and laboratory hints that allow physicians to diagnose TTP and HIT efficiently and offer patients the best available therapeutic interventions are presented.