Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) represents a stress test for tumor cells and T cells. Mechanisms exist that allow cells to survive this stress, including suboptimal target block, alternative signaling pathways, and autophagy. Rapamycin-resistant effector T (T-Rapa) cells have an altered phenotype that associates with increased function. Ex vivo rapamycin, when used in combination with polarizing cytokines and antigen-presenting-cell free costimulation, is a flexible therapeutic approach as polarization to T-helper 1 (Th1)- or Th2-type effectors is possible. Murine T-Rapa cells skewed toward a Th2-type prevented graft rejection and graft-versus-host disease (GVHD) more potently than control Th2 cells and effectively balanced GVHD and graft-versus-tumor (GVT) effects. A phase II clinical trial using low-intensity allogeneic hematopoietic cell transplantation demonstrated that interleukin-4 polarized human T-Rapa cells had a mixed Th2/Th1 phenotype; T-Rapa cell recipients had a balanced Th2/Th1 cytokine profile, conversion of mixed chimerism toward full donor chimerism, and a potentially favorable balance between GVHD and GVT effects. In addition, a phase I clinical trial evaluating autologous T-Rapa cells skewed toward a Th1- and Tc1-type is underway. Use of ex vivo rapamycin to modulate effector T-cell function represents a promising new approach to transplantation therapy.