Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development. Complement blockade using eculizumab has shown some promising rates of hematologic responses, however, survival may still be poor. Early discontinuation of calcineurin inhibitor where feasible, use of eculizumab, aggressive infection prophylaxis, close monitoring and early treatment of potential complications including GvHD and organ failure may improve outcomes. A number of complement inhibitors are in the development and may change treatment paradigm. Future studies are important to better understand TA-TMA as a disease process and may aim to confirm the role of complement activation in TA-TMA, enhance diagnostic strategy, determine therapeutic approaches and strategies to reduce the risk of other complications particularly infection and GvHD.