Advances in maintenance immunosuppression over the past decade has resulted in dramatic improvements in short- and long-term outcomes in organ transplantation as well as a decreased incidence of acute rejection. However, immunosuppressive drugs need to be given long term, lack specificity, and are accompanied by adverse metabolic derangements, toxicities, the risk of infection and cancer, and a myriad of other side effects. Further, they fail to prevent and control chronic rejection. This review will outline a number of immunosuppressive agents that are currently being explored in experimental and clinical transplantation. These include biologic agents that have more specificity and selectivity, and are aimed at T-cell depletion, blockade of costimulation, adhesion markers, or at novel targets. Most of the studies have been limited to adults but should be applied to the pediatric population as well.