Lancet 2017;389:2328–37 DOI 10.1016/S0140-6736(17)31472-1This review paper examines the understanding gained from looking at the effects of specific immune interventions in the treatment of RA.The introduction of novel IL-6 agents has provided the ideal opportunity to explore the distinct effect of cytokine inhibition, as opposed to receptor inhibition, at the molecular level. Mechanistic insights into TNF could also be obtained in the future with advanced molecular and informatics approaches, and future biopsy studies will be important to explore the biology of the emerging class of JAK inhibitors and to dissect JAK pathway selectivity.Several cytokine inhibitors have been unsuccessful in RA (IL-1, IL-17A inhibition or IL-17A receptor inhibition, p40 or IL-23) – these cytokines not having a sufficiently important hierarchical/non-redundant role for their inhibition to diminish disease.While there is evidence of a pivotal pathological role for GM-CSF in RA, there are no agents targeting this cytokine yet approved for clinical use. There is renewed interest in targeting T-cell-dependent effector and regulatory pathways and re-establishing immune homoeostasis. The revolution in therapeutics for immune and signalling pathways has led to pathogenetic understanding offering the possibility of modifying established inflammatory processes by immune modulatory cells. The future challenge is to build on these observations to achieve the ultimate ambition – immunological homoeostasis and drug-free remission.