The JAK-STAT pathway is a critical signaling mechanism that transmits signals from the extracellular environment to the nucleus, playing a vital role in physiological functions such as hematopoiesis, immune balance, tissue homeostasis, and tumor surveillance. Dysregulation of this pathway can lead to various diseases, including immune deficiencies, autoimmune disorders, and cancer. Extensive research has been conducted on this pathway, ranging from basic research to medical applications. Advances in structural biology have provided insights into the molecular mechanisms of the signaling cascade, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced understanding of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed the engineering of cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. The JAK-STAT pathway is a paradigm for signal transduction, with its activation initiated by specific molecular interactions between cytokines and receptors, leading to receptor dimerization or multimerization, which activates JAKs, subsequent phosphorylation of STATs, and initiation of transcriptional events. However, when this pathway becomes dysregulated, it can have significant implications for cellular processes and contribute to the pathogenesis of diseases such as immunodeficiency, inflammatory and autoimmune conditions, hematological disorders, and cancer. Given its broad effects on human biology and disease, the JAK-STAT pathway has emerged as an attractive target for the treatment of various disorders. Over the past three decades, significant progress has been made in advancing this pathway from basic research to medical applications. One notable aspect of this advancement involves a fundamental understanding of the pathway through the lens of structural biology. The evolution of technologies like cryo-electron microscopy (cryo-EM) has propelled three-dimensional (3D) structural studies on proteins, including those integral to the JAK-STAT pathway. These technological breakthroughs have empowered us to visualize and scrutinize the intricate details of large protein complexes at near-atomic resolution, offering invaluable insights into the functional mechanisms of key signaling molecules. The elucidation of the structures of cytokines, receptors, JAKs, and STATs provides insights into the molecular mechanisms governing cytokine-receptor recognition, pathway activation, and gene transcription. This enhanced understanding of the structure and molecular mechanisms within the JAK-STAT signaling has given rise to another promising field: cytokine engineering, which aims to tailor cytokines for a wide array of medical applications. The JAK-STAT pathway is involved in various biological functions, including the differentiation and maturation of blood cell lineages, maintaining a balanced hematopoietic system, and regulating the development, activation, and function of immune cells. Genetic variations in genes encoding cytokines, cytokine receptors, JAKs, and STATs have been identified as risk factors for immunodeficiencies and autoimmune disorders. Mutations in JAK3 and TYK2 have been associated with primary immunThe JAK-STAT pathway is a critical signaling mechanism that transmits signals from the extracellular environment to the nucleus, playing a vital role in physiological functions such as hematopoiesis, immune balance, tissue homeostasis, and tumor surveillance. Dysregulation of this pathway can lead to various diseases, including immune deficiencies, autoimmune disorders, and cancer. Extensive research has been conducted on this pathway, ranging from basic research to medical applications. Advances in structural biology have provided insights into the molecular mechanisms of the signaling cascade, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced understanding of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed the engineering of cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. The JAK-STAT pathway is a paradigm for signal transduction, with its activation initiated by specific molecular interactions between cytokines and receptors, leading to receptor dimerization or multimerization, which activates JAKs, subsequent phosphorylation of STATs, and initiation of transcriptional events. However, when this pathway becomes dysregulated, it can have significant implications for cellular processes and contribute to the pathogenesis of diseases such as immunodeficiency, inflammatory and autoimmune conditions, hematological disorders, and cancer. Given its broad effects on human biology and disease, the JAK-STAT pathway has emerged as an attractive target for the treatment of various disorders. Over the past three decades, significant progress has been made in advancing this pathway from basic research to medical applications. One notable aspect of this advancement involves a fundamental understanding of the pathway through the lens of structural biology. The evolution of technologies like cryo-electron microscopy (cryo-EM) has propelled three-dimensional (3D) structural studies on proteins, including those integral to the JAK-STAT pathway. These technological breakthroughs have empowered us to visualize and scrutinize the intricate details of large protein complexes at near-atomic resolution, offering invaluable insights into the functional mechanisms of key signaling molecules. The elucidation of the structures of cytokines, receptors, JAKs, and STATs provides insights into the molecular mechanisms governing cytokine-receptor recognition, pathway activation, and gene transcription. This enhanced understanding of the structure and molecular mechanisms within the JAK-STAT signaling has given rise to another promising field: cytokine engineering, which aims to tailor cytokines for a wide array of medical applications. The JAK-STAT pathway is involved in various biological functions, including the differentiation and maturation of blood cell lineages, maintaining a balanced hematopoietic system, and regulating the development, activation, and function of immune cells. Genetic variations in genes encoding cytokines, cytokine receptors, JAKs, and STATs have been identified as risk factors for immunodeficiencies and autoimmune disorders. Mutations in JAK3 and TYK2 have been associated with primary immun