An increasing number of individuals with end-stage renal disease have become sensitized to human leukocyte antigens (HLA). Sensitization can have a profound impact on the likelihood of obtaining a requisite negative crossmatch (-XM) with a potential donor. Technologic breakthroughs in our ability to diagnose antibody-mediated rejection (AMR) and monitor anti-HLA antibodies has set the stage for a renascence in the understanding and treatment of individuals who harbor donor-specific antibody (DSA). Promising early results from single institutions that have developed preconditioning protocols allowing successful transplantation of XM (+) patients have encouraged other centers to adopt these protocols. Sensitized patients represent a great challenge for the clinician and there is much that remains unknown about the assessment and treatment of these patients. We have successfully preconditioned and transplanted more than 80 patients over a 5-yr period. As our understanding of these patients has increased, we have progressed from a 'one size fits all' approach to therapy to more rational, individualized treatment plans that take into account the varying immunologic risk that each patient possesses. In this article we have summarized our evolving experience with the assessment, treatment, transplantation, and monitoring of patients who undergo preconditioning for a (+) XM with a live donor.