Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases.