Recent findings suggest that a chronic alloimmune response is playing the dominant role in late allograft loss, challenging the notion that most grafts are lost due to the inexorable progression of calcineurin inhibitor (CNI) nephrotoxicity. CNIs have failed to improve long-term outcomes and are associated with multiple metabolic derangements. Thus, improvement in long-term allograft outcomes may depend on new agents with novel mechanisms of action, devoid of the toxicities associated with CNIs. To meet this need, inhibitors of novel pathways in B cell and plasma cell activation have emerged to combat the humoral immune response including belimumab and atacicept, both promising targets of B-cell survival factors and bortezomib and eculizumab, agents currently in trials for desensitization protocols and treatment of antibody-mediated rejection. Promising agents for maintenance immunosuppression, used as monotherapy or synergistically, include monoclonal antibodies and fusion receptor proteins targeting the CD40-CD154 pathway (multiple anti-CD40 antibodies), the CD28-CD80/86 pathway (ie, belatacept), the LFA3-CD2 pathway (ie, alefacept), and small molecules such as tofacitinib, a janus kinase 1/3 inhibitor. The induction of allograft tolerance has been attempted with some success with simultaneous bone marrow/kidney transplantation from the same donor, albeit, limited by its associated toxicites. Finally, the exciting fields of tissue engineering and stem cell biology with the repopulation of decellularized organs is ushering in a new paradigm for transplantation. The era of simplified immunosuppression regimens devoid of toxicities is upon us with the promise of dramatic improvement in long term survival.