Left ventricular assist devices (LVADs) have become an established surgical therapy for patients with end-stage heart failure who require hemodynamic support as a bridge-to-transplant or destination therapy. However, the anatomic and physiologic consequences of long-term LVAD support have yet to be fully clarified. Despite the clinical success of these devices, it has been reported that many patients bridged to transplantation with mechanical support develop circulating antibodies with potential donor reactivity. Transplanting against existing or historic donor-specific antibodies is associated with increased risk of antibody-mediated rejection, graft dysfunction, and decreased survival. Safe transplantation of allosensitized patients is dependent on using prospective crossmatching and antibody titer reduction techniques (desensitization). Strict protocols requiring a negative prospective crossmatch before transplantation result in a decreased donor pool and a longer duration of support in sensitized LVAD recipients with increased inherent morbidity such as infections and thromboembolic complications. The aim of this review is to present the current state of knowledge of possible immunologic mechanisms involved in alloimmunization of LVAD recipients, outline new methods of antibody detection, compare various desensitization strategies, and present an overview of clinical data assessing the impact of sensitization on posttransplantation outcome.