The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway transmits information received from extracellular polypeptide signals, through transmembrane receptors, directly to transcription factors that bind target gene promoters in the nucleus. This process provides a mechanism for transcriptional regulation without second messengers. Evolutionarily conserved in eukaryotic organisms from slime molds to humans, JAK-STAT signaling appears to be an early adaptation to facilitate intercellular communication that has coevolved with myriad cellular signaling events. This coevolution has given rise to highly adapted, ligand-specific signaling pathways that control gene expression. In addition, the JAK-STAT signaling pathways are regulated by a vast array of intrinsic and environmental stimuli, which can add plasticity to the response of a cell or tissue. The Connections Map provides a generalized view of this JAK-STAT signaling, with additional Connections Maps highlighting the components that are activated by type I interferons (IFN-α/β), IFN-γ, and interleukins and growth factors that activate STAT3.