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Posttransplant donor-specific human leukocyte antigen (HLA) antibodies (DSA) represent a complex area in heart transplantation with nonstandardized practice and paucity of clinical data to guide optimal management.De novo DSA after heart transplantation is common and associated with rejection, cardiac allograft vasculopathy, allograft failure, and mortality. Advances in methods for HLA antibody detection have enabled identification of DSA with high precision and sensitivity. The detection of HLA antibodies must, however, be interpreted within appropriate laboratory and clinical contexts; it remains unclear which DSA are associated with greatest clinical risk. Increased antibody and clinical surveillance as well as optimization of maintenance immunosuppression are required for all patients with DSA. Antibody-directed therapies are reserved for patients with allograft dysfunction or rejection. Treatment of DSA may also be considered in asymptomatic high-risk patients including those in whom DSA arise de novo posttransplant, is persistent, high titer, or complement activating. The impact of DSA reduction and removal on long-term clinical outcomes remains unknown.Despite improvements in DSA detection, identification, and characterization, best therapeutic strategies are unclear. Prospective multicenter studies are needed to develop effective standardized approaches for DSA management in heart transplantation.