Human leukocyte antigen (HLA) sensitization and ABO incompatibility continue to pose significant barriers to further expansion of live donor renal transplantation. However, the recent development of effective desensitization protocols and creative paired donation strategies demonstrates that the presence of circulating donor HLA-specific antibodies and the use of ABO incompatible organs should no longer be considered contraindications for renal transplantation. It is estimated that as many as 6,000 patients on the kidney transplant waiting list have incompatible living donors and could benefit from these treatments. Furthermore, as our understanding of these treatment modalities has improved, it is now possible to predict whether desensitization, kidney paired donation or a combination of both will provide an individual patient with their best chance for successful renal transplantation.