The Janus kinase/signal transducer and activator of transfection (JAK/STAT) system is comprised of multiple cell surface receptors, receptor tyrosine kinases, and signal transducers that are key components of numerous systems involved in malignancy, inflammation, immune surveillance and development, cellular proliferation, metabolism, differentiation, apoptosis, and hematologic disorders, all of which when disrupted can produce severe disease. Nevertheless, small molecule inhibitors of the four known JAKs, termed JAKinibs, have found therapeutic indications for a broad category of diseases. In this perspective, I will summarize the development of JAK inhibitors, whose origins were in antiquity, with particular attention to their use in treating patients with inflammatory bowel disease (IBD). This perspective is accompanied by a companion publication addressing how JAKinibs have forever altered the landscape of IBD therapy.