Nature Reviews Rheumatology 2013; 9(3):173-82This review paper considers how advances in understanding of the disease process underlying rheumatoid arthritis (RA) and the development of novel techniques have transformed the management of this progressively disabling condition. Physicians are no longer limited to prescribing symptomatic treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) or choosing from a seemingly random array of drugs drawn from multiple disciplines, such as methotrexate and sulphasalazine, which are described under the umbrella term 'synthetic disease-modifying antirheumatic drugs (DMARDs)’. Advances in molecular biology, biochemistry and monoclonal antibody technology over the past 20 years have brought about the introduction of ‘biological DMARDs’ in the form of tumour necrosis factor inhibitors, which have markedly improved outcomes in RA. The authors acknowledge that as understanding of receptor biology and signal transduction pathways continues to evolve, it seems increasingly possible that we will be able to invoke stronger and longer-lasting responses. This review looks ahead to the new generation of targeted therapies, including inhibitors of JAK, SYK, BTK, PI3K, PKB, mTOR and MAPK, discussing their modes of action and the evidence available from trials to date on efficacy and safety.