 Abstract the Janus Kinasek signal transducer and activator of transcription, JAK-STAP, signaling pathway was discovered more than a quarter century ago. As a fulcrum of many vital cellular processes, the JAK-STAP pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK-STAP pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK-STAP pathway. Moreover, we highlight the role of the JAK-STAP pathway and its inhibitors in various diseases. This article was authored by Sherry Hu, Jing Li, Ma Rang Fu, and others.