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The aim of this review is to discuss the impact of antibody sensitization on heart transplant recipients.We will discuss the current state of antibody identification, antibody strength and potential antibody pathogenicity. The prevalence of antibody sensitization has increased with increased utilization of mechanical circulatory support (MCS). Data on MCS-related antibody sensitization are reviewed. Important considerations to minimize the prozone effect in antibody testing will be discussed. We present an overview of strategies for desensitization in solid organ transplantation. Current protocols for desensitization therapies will be presented. Finally, future research avenues, including potential further refinement of the detection of human leukocyte antigen (HLA) epitopes to improve donor–recipient immunologic matching, future direction for prevention of donor-specific antibodies (DSAs), the potential role of non-HLA antibodies and further potential refinement of the immune system for management of sensitized patient will be proposed.Antibody sensitization is a key immunologic issue prior to and after heart transplantation. Therapies aimed at immunomodulation, termed desensitization strategies, may improve immunologic matching at the time of heart transplantation.