One of the therapeutic approaches to type 1 diabetes (T1D) focuses on enhancement of regulatory T cell (Treg) activity, either by adoptive transfer or supplementation of supporting cytokines such as interleukin-2 (IL-2). In principle, this therapeutic design would greatly benefit of concomitant reduction in pathogenic cell burden. Experimental evidence indicates that physiological recovery from lymphopenia is dominated by evolution of effector and cytotoxic cells, which abolishes the therapeutic efficacy of Treg cells. Targeted and selective depletion of effector T cells has been achieved with killer Treg using Fas ligand protein and a fusion protein composed of IL-2 and caspase-3, which showed remarkable efficacy in modulating the course of inflammatory insulitis in NOD mice. We emphasize a critical consideration in design of therapeutic approaches to T1D, immunomodulation without lymphoreduction to avoid the detrimental consequences of rebound recovery from lymphopenia.