The γc family of cytokines (IL-2, IL-4, IL-7, IL-9 IL-15, and IL-21) collectively regulate normal development, growth, differentiation, and survival of lymphocytes. When dys-regulated signaling occurs, this can result in disease, including for example, severe combined immunodeficiency and autoimmunity. Like other type I cytokines, γc family cytokines activate STAT proteins and different cytokines can exhibit opposing actions when they activate different STAT proteins. Interestingly, IL-21 can also differentially use either STAT1 versus STAT3, which can result in the fine-tuning of signals induced by IL-21. Moreover, IL-2 can induce STAT5 dimerization versus tetramerization as another physiological mechanism for fine-tuning signaling. STAT5 tetramerization is critical for normal proliferation of T cells in vitro and in vivo and for the development of normal numbers of CD8 T cells and natural killer cells. In the absence of STAT5 tetramers, NK cells exhibit dys-regulated expression of genes involved in survival and CD8 T cells exhibit defective regulation of genes involved in cell cycle progression. In addition to these physiological mechanisms of fine-tuning, with Chris Garcia’s lab at Stanford, we have created and studied novel IL-2 partial agonists that can fine tune IL-2 signaling. These molecules can attenuate receptor heterodimerization and inhibit STAT5 activation and gene expression, with one of these molecules having the ability to augment survival of animals in a mouse model of graft versus host disease and to inhibit the proliferation ex vivo of leukemic cells from patients with the chronic-smoldering form of adult T cell leukemia. Thus, we provide both physiological and pharmacological ways of fine-tuning signaling of γc family cytokines to regulate the immune system.