Transplantation of cells, tissues and vascularized solid organs is a successful therapeutic intervention for many end-stage chronic diseases. The combination of co-stimulatory blockade with the delivery of negative signals to T cells through co-inhibitory receptors would provide a robust approach to modulating T-cell receptor signaling and improving alloantigen-specific control of transplant rejection. This approach based on fundamental knowledge of APC/T-cell interactions may complement conventional therapies in the near future to reinforce long-term allograft survival, and permit minimal immunosuppression. The focus of this review was primarily on two major co-inhibitory signaling pathways, namely PD-1/PD-L1/PD-L2 and BTLA/CD160/HVEM/LIGHT that have been thoroughly characterized in murine models of transplantation using genetically modified mice, specific monoclonal antibodies and fusion proteins.