© 2016, Springer. All rights reserved. Purpose of Review Renal transplantation offers a significant survival benefit over dialysis for patients with end-stage renal disease. Furthermore, transplantation with a living donor kidney offers superior survival when compared to a deceased donor. However, supply of trans-plantable kidneys continues to fall short of demand; living donation offers a solution to help decrease this disparity. For those patients who have willing donors, many will be incompatible secondary to blood group or tissue mis-matches. In this setting, a crucial decision must be made— pursue living donor transplantation by overcoming the incompatibility through desensitization or kidney paired donation, or wait on the deceased donor transplant list for a compatible kidney to become available. Recent Findings This review explores the regimens for desensitization, clinical outcomes, and potential adverse sequelae for both tissue incompatibility [that is, patients with anti-human leukocyte antigen (anti-HLA) antibodies] and blood group (ABO) incompatibility. This review also summarizes the different strategies involved in kidney paired donation (KPD) and addresses challenges unique to this model of transplantation. Summary The decision to utilize desensitization versus KPD is an individualized one, guided by donor and recipient characteristics and preferences.