Activation of cytokine receptor-associated Janus kinases (JAKs) mediates most, if not all, of the cellular responses to peptide hormones and cytokines. Consequently, JAKs play a paramount role in homeostasis and immunity. Members of this family of tyrosine kinases control the cytokine/hormone-induced alterations in cell gene expression program. This function is largely mediated through an ability to signal toward activation of the signal transducer and activator of transcription proteins (STAT), as well as toward some other pathways. Importantly, JAKs are also instrumental in tightly controlling the expression of associated cytokine and hormone receptors, and, accordingly, in regulating the cell sensitivity to these cytokines and hormones. This review highlights the enzymatic and non-enzymatic mechanisms of this regulation and discusses the importance of the ambidextrous nature of JAK as a key signaling node that integrates the combining functions of forward signaling and eliminative signaling. Attention to the latter aspect of JAK function may contribute to emancipating our approaches to the pharmacological modulation of JAKs. J. Cell. Biochem. 115: 8–16, 2014. © 2013 Wiley Periodicals, Inc.