Cytokines are key mediators of the development and homeostasis of haematopoietic cells, critical for host defense, but also for the development of autoimmune and inflammatory diseases such as psoriasis or rheumatoid arthritis (RA). Blocking cytokines activity by interfering with the ligand–receptor association has been successfully employed to treat several immune disorders. A subgroup of cytokines signals through receptors requiring the association with a family of cytoplasmic protein tyrosine kinases known as Janus kinases (Jaks). Jaks have recently gained significant attention as therapeutic targets in inflammation and autoimmunity, and several Jak inhibitory small molecules have been developed. The first two Jak inhibitors, tofacitinib and ruxolitinib, have been approved for the treatment of RA and primary myelofibrosis, respectively. Efficacy and safety data suggest that some of these oral Jak inhibitors as well as their topical formulations may soon enter the daily clinical practice for treating patients with psoriasis, lupus erythematosus or other inflammatory skin diseases. While biologics typically target one single cytokine, these new immunomodulators can inhibit signals from multiple cytokines intra-cellularly and therefore could be useful when other therapies are ineffective. Thus, Jak inhibitors may replace some traditional immunosuppressive agents and help patients not responding to previous therapies.