This Practice Point commentary discusses the experience of Shapiro et al. with renal allograft recipients at a single center who underwent significant minimization of immunosuppressive treatment with alemtuzumab induction and tacrolimus monotherapy (weaned to three times weekly by 1 year after transplantation). Donor-specific antibodies (DSAs) against human leukocyte antigen were monitored after transplantation in some patients. Although 44% of patients did not develop acute rejection or DSAs and had excellent 2-year graft survival (96%), spaced weaning was not attempted in 20% of patients, generally those with early rejection and poor allograft function. During tapering, 20% of patients developed acute rejection and 15% developed DSAs. Two-year graft survival was 63% in patients for whom weaning was not attempted and 78% in patients who experienced acute rejection. Alemtuzumab preconditioning with tacrolimus monotherapy and spaced weaning increased the risk of acute rejection and development of DSAs. Patients should be carefully selected for this protocol and monitored closely for DSAs. Results of a long-term controlled trial that includes protocol biopsies are required to reach more-definitive conclusions.