Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation in which systemic complement activation induces endothelial injury, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction. TA-TMA often progresses rapidly and has historically been associated with high mortality. Over the last decade, increasing recognition of complement activation as a central driver of TA-TMA has shifted management from largely empirical supportive care toward mechanism-based therapy. This review summarizes recent advances in complement-targeted therapies for TA-TMA and outlines key aspects of pathophysiology, risk factors, and monitoring that inform therapeutic decision-making. Earlier non–complement-directed therapies, including calcineurin inhibitor modification, plasma exchange, defibrotide, and rituximab, showed limited and inconsistent benefit. In contrast, complement-targeted therapies have advanced the treatment of TA-TMA. Prospective and large cohort data support the clinical activity of eculizumab (C5 inhibitor), with meaningful improvements in survival and organ recovery. Ravulizumab (long-acting C5 inhibitor) has shown encouraging phase 3 results, and narsoplimab (MASP-2 inhibitor), which became the first approved treatment for TA-TMA, has demonstrated promising outcomes, including activity in some patients previously exposed to C5 inhibition. In addition, newer agents targeting C5, C3, or factor B are expanding the therapeutic horizon for TA-TMA, although efficacy data are still limited for some of these therapies. Overall, complement-targeted therapies represent a therapeutic advance in TA-TMA, and ongoing prospective studies will be crucial to define optimal agent selection, sequencing, and integration into clinical practice.