Advances in the treatment of RA in the past decade have been achieved mainly by using combinations of different conventional and biologic DMARDs. However, until now no final victory has been achieved over this organ damaging and potentially life-threatening systemic autoimmune disease. Few patients, notably those with established disease, stay in remission permanently, even using advanced treatment concepts. Thus novel approaches, especially for patients resistant to biologics, are urgently needed. Pro-inflammatory signalling pathways beyond the level of cytokines and receptors have been intensively elaborated and provide such potential targets. This review focuses on the development of new small molecule inhibitors of Janus kinases in clinical trials in RA.