The first decade of the new millennium has been disappointing for transplant therapeutics: no new immunosuppression agents have been approved. Several high profile drugs and biologics failed the rigors of clinical trials or had disappointing preclinical results (FTY720, FK778, anti-CDI54, anti-IL15, anti-CD28, R3421). Several challenges face the industry and clinical investigators in bringing novel drugs to the clinic including the difficulty in targeting new endpoints for toxicities or chronic allograft disease since acute rejection has been reduced to below 15% as well as the Food and Drug Administration insistence of excluding the use of immunosuppression regimens embraced by the transplant community in control arms of clinical trials. Currently six new agents, 3 small molecules (ISA247, a semisynthetic analogue of cyclosporine; AEB071, a protein kinase C isoforms inhibitor; CP 690,550, a selective Janus kinase inhibitor) are in phase II trials and 3 biologics (belatacept, a second generation CTLA4Ig; efalizumab, a humanized antiCD11a [LFA1] monoclonal antibody; and alefacept, a LFA3-IgG1 fusion receptor protein) are in phase II/III clinical trials. The preclinical pipeline is not only full but promises to address previously neglected targets and fulfill unmet medical needs in transplant therapeutics.