PURPOSE OF REVIEW: Current immunosuppressive therapies are highly successful at regulating acute allograft rejection and inducing long-term transplanted kidney survival; however, currently available medications are associated with generalized immune suppression and drug toxicities, including nephrotoxicity. In recent years, advances in immunosuppression that target specific pathways involved in immune activation have been developed. RECENT FINDINGS: In particular, promising medications are currently under evaluation that target ischemia-reperfusion injury as well as the cellular and humoral branches of the adaptive immune response. Targets of T-cell-mediated activation include antibodies and fusion proteins interfering with LFA-1/ICAM-1, CD2/LFA-3, CD40/CD154, and CD28/B7.1 and B7.2 interactions. Intracellular targets involved in T- and B-cell activation pathways are being evaluated, including protein kinase C inhibitors, Janus-associated kinase (JAK) inhibitors, and proteasome inhibitors. Several new medications demonstrate promise in inhibiting donor-directed humoral immunity by targeting B-cell-activating factor (BAFF) and complement activation pathways. SUMMARY: The present review evaluates the recent clinical advances in immunosuppressive therapies for kidney transplantation. Publications regarding advances in immunosuppressive therapies over the past year were evaluated in the context of the specific immune pathways involved in allograft rejection.