Platelet transfusion refractoriness can be challenging to manage. There is no simple “One Solution” that solves all in platelet refractoriness management. Platelet transfusion has been a mainstay of treatment for patients who become thrombocytopenic due to cancer, malignant hematological disease, and hematopoietic stem cell transplant. However, patients who receive multiple units may develop platelet refractoriness in 15-25% of cases. The more units these patients receive, the more likely they are to receive multiple antibodies, which makes finding the next match more difficult. Patients with high HLA antibodies and a high calculated panel reactive antibody (cPRA) may face long delays in acquiring adequate units, increasing the risk of severe hemorrhage. In this session, we will discuss a variety of treatments for patients who become increasingly alloimmunized and refractory to treatment. We will first discuss the available testing options for performing crossmatching and detecting HLA/HPA antibodies. We will then discuss the progression of transfusion components available from “Good Response” donors, and platelet crossmatches to HLA-compatible and HLA-matched platelets. Finally, we will discuss more novel options for the highly immunized patient, including twenty-four-hour continuous random platelet transfusion, vincristine-infused platelets, Eculizumab therapy, and novel neonatal Fc receptor blockers (Efgartigimod and Rozanolixizumab).