In the clinical arena of transplantation, tolerance remains, for the most part, a concept rather than a reality. Although modern immunosuppression regimens have effectively handled acute rejection, nearly all organs except the liver commonly suffer chronic immunologic damage that impairs organ function, threatening patient and allograft survival. In addition to the imperfect control of the donor-directed immune response, there are additional costs. First, there is the burden of mortality from infection and malignancy that can be directly attributed to a crippled immune system. Second, there are insidious effects on renal function, cardiovascular profile (hypertension, hyperglycemia, and dyslipidemia), bone health, growth, psychological and neurocognitive development, and overall quality of life. It is likely that the full consequences of lifelong immunosuppression on our pediatric transplant recipients will not be fully appreciated until survival routinely extends beyond 1 or 2 decades after transplantation. Therefore, it can be argued that the holy grail of transplantation tolerance is of the utmost importance to children who undergo solid organ transplantation.