Maintaining T cell homeostasis is critical for normal immune response. Three sequential signals activate T cells, with signal 3 delivered by multiple cytokines that regulate cell proliferation, differentiation, and survival/death. Cytokines binding to their receptors engages two key molecular families, namely, Janus tyrosine kinases (Jaks) and signal transducers and activators of transcription (Stats). Among Stats, Stat3 is involved in the generation of T helper 17 (Th17) cells, regulation of dendritic cells, and acute inflammatory response. These aspects of Stat3 function are important for transplantation. We discuss Stat3's role in innate and adaptive immunity as well as its potential for therapeutic intervention.