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Antibody allosensitization poses a major immunologic challenge for patients awaiting heart transplantation. It is associated with significant morbidity and mortality for both pretransplant and posttransplant patients by prolonging wait times to transplant and increasing posttransplant rejection and vasculopathy. Many questions remain regarding methods and interpretation of antibody detection, the relevance of sensitization in specific patient populations such as those with mechanical circulatory support and the ideal strategies for desensitization.More sensitive and specific assays are now available to help identify and risk stratify highly sensitized patients. The growing field of mechanical circulatory support is introducing new questions and observations about sensitization in patients supported by ventricular-assist devices. Multiple desensitization therapies, including newer treatments such as bortezomib and eculizumab, targeting various components of the humoral immune response, appear to show promise by significantly reducing allosensitization and allowing for successful transplantation with good outcomes.The development of more accurate methods of detecting sensitization and defining the ideal desensitization strategies that can be more universally adopted and tested in clinical trials will serve to enlighten us and help many more highly sensitized patients not only make it to transplant, but also thrive posttransplant as well.