The interleukin-2 (IL-2) and interleukin-2 receptor (IL-2R) system plays a central role in both the innate and adaptive arms of the immune response. Of major importance is the function of IL-2/IL-2R in the activation, differentiation, expansion, and maintenance of T cells that are critical to adaptive immunity. Clinically, the IL-2/IL-2R axis has been linked to the development and persistence of hematopoietic malignancies, autoimmune disorders, and allograft rejection. As such, the IL-2/IL-2R system has been extensively studied and exploited for T-cell directed immunotherapy. Several immunomodulatory approaches targeting this receptor system have been developed that include antibody-based ligands and radioisotopes, as well as immunoglobulin and cytokine chimeric biologics, which contain toxins and apoptosis-inducing proteins. While some of these biologics are already in clinical practice others are either in transition to the clinic or under development. We herein review the effectiveness and limitations of these biologics and discuss new strategies that could minimize the limitations and improve on the efficacy of IL-2R-targeted immunotherapy.