By exploiting mechanisms of immunological regulation against donor alloantigen, it may be possible to reduce the dependence of kidney transplant recipients upon calcineurin inhibitor-based maintenance immunosuppression. One means to strengthen regulatory responses is treating recipients with preparations of regulatory cells obtained by ex vivo manipulation. This strategy, which is a well-established experimental method, has been developed to the point that early-phase clinical trials in kidney transplantation are now feasible. Cell-based therapies represent a radical departure from conventional treatment, so what grounds are there for this new approach? This article offers a three-part justification for trialing cell-based therapies in kidney transplantation: first, a clinical need for alternatives to standard immunosuppression is identified, based on the inadequacies of calcineurin inhibitor-based regimens in preventing late allograft loss; second, a mechanistic explanation of how cell-based therapies might address this clinical need is given; and third, the possible benefit to patients is weighed against the potential risks of cell-based immunosuppressive therapy. It is concluded that the safety of cell-based immunosuppressive therapy will not be greatly improved by further basic scientific and preclinical development. Only trials in humans can now tell us whether cell-based therapy is likely to benefit kidney transplant recipients, but these should be conservative in design to minimize any potential harm to patients.