The review discusses the role of Janus kinases (Jaks) in immune cell signaling and their involvement in various immune disorders. Jaks, including Jak1, Jak2, Jak3, and Tyk2, are non-receptor protein tyrosine kinases crucial for cell growth, survival, development, and differentiation. Deficiency of Jak3 or Tyk2 results in specific clinical disorders, such as severe combined immunodeficiency syndrome and autosomal recessive hyperimmunoglobulin E syndrome, respectively. In contrast, complete deletion of Jak1 or Jak2 is incompatible with life. Activating mutations in Jaks are associated with malignant transformation, particularly in polycythemia vera and other myeloproliferative disorders. The Jak-STAT pathway, which involves the activation of STAT proteins, is a key mechanism through which Jaks exert their effects. The review also highlights the regulatory mechanisms of Jaks, including phosphorylation and interactions with other proteins, and their functional consequences in immune cell signaling. Additionally, it discusses the clinical implications of Jak mutations in human diseases and the development of Jak inhibitors as therapeutic agents for autoimmune diseases and malignancies.The review discusses the role of Janus kinases (Jaks) in immune cell signaling and their involvement in various immune disorders. Jaks, including Jak1, Jak2, Jak3, and Tyk2, are non-receptor protein tyrosine kinases crucial for cell growth, survival, development, and differentiation. Deficiency of Jak3 or Tyk2 results in specific clinical disorders, such as severe combined immunodeficiency syndrome and autosomal recessive hyperimmunoglobulin E syndrome, respectively. In contrast, complete deletion of Jak1 or Jak2 is incompatible with life. Activating mutations in Jaks are associated with malignant transformation, particularly in polycythemia vera and other myeloproliferative disorders. The Jak-STAT pathway, which involves the activation of STAT proteins, is a key mechanism through which Jaks exert their effects. The review also highlights the regulatory mechanisms of Jaks, including phosphorylation and interactions with other proteins, and their functional consequences in immune cell signaling. Additionally, it discusses the clinical implications of Jak mutations in human diseases and the development of Jak inhibitors as therapeutic agents for autoimmune diseases and malignancies.