The article provides a comprehensive overview of the JAK-STAT pathway, highlighting its discovery, development, and recent advancements. The pathway, initially identified as crucial for the cellular response to type I interferons (IFNs), has since been expanded to include type II IFNs and other cytokines. The authors, George R. Stark and James E. Darnell Jr., recount their collaborative efforts in uncovering the pathway, emphasizing the importance of posttranslational modifications such as serine phosphorylation, acetylation, methylation, and sumoylation of STAT proteins. They also discuss the non-canonical functions of STAT proteins, including their roles in mitochondrial respiration and chromatin organization. The article traces the historical milestones, from the early studies on interferon induction to the identification of key components like TYK2, JAK1, and STAT proteins. It highlights the significance of mutant cell lines in identifying essential proteins and their functions, and it reviews the completion of the JAK-STAT family, with the discovery of seven STAT proteins. The authors also explore the broader context of cell signaling, comparing the JAK-STAT pathway to other signaling pathways and discussing the involvement of STAT proteins in various cellular functions and diseases.The article provides a comprehensive overview of the JAK-STAT pathway, highlighting its discovery, development, and recent advancements. The pathway, initially identified as crucial for the cellular response to type I interferons (IFNs), has since been expanded to include type II IFNs and other cytokines. The authors, George R. Stark and James E. Darnell Jr., recount their collaborative efforts in uncovering the pathway, emphasizing the importance of posttranslational modifications such as serine phosphorylation, acetylation, methylation, and sumoylation of STAT proteins. They also discuss the non-canonical functions of STAT proteins, including their roles in mitochondrial respiration and chromatin organization. The article traces the historical milestones, from the early studies on interferon induction to the identification of key components like TYK2, JAK1, and STAT proteins. It highlights the significance of mutant cell lines in identifying essential proteins and their functions, and it reviews the completion of the JAK-STAT family, with the discovery of seven STAT proteins. The authors also explore the broader context of cell signaling, comparing the JAK-STAT pathway to other signaling pathways and discussing the involvement of STAT proteins in various cellular functions and diseases.