By definition, tolerance will eliminate the problem of adolescent medication non-adherence. Although adolescents' propensity toward non-adherence makes them at first glance to be particularly attractive candidates for tolerance trials, there are also immunologic, psychosocial and ethical barriers that temper enthusiasm for their inclusion at present. Limits in emotional and cognitive maturity are combined during the teenage years with adult-like immunologic maturity to lessen the potential for successful implementation of tolerance and near tolerance strategies. Alternatively, an interval step to tolerance in adolescents is to eliminate the medications most likely contributing to non-adherence through harsh side effects such as steroids and calcineurin inhibitors. This manuscript will review the general topic of transplantation tolerance with specific attention given to the application of pro-tolerant therapies in adolescent recipients.