Rheumatoid arthritis (RA) is a multifactorial immune disease exhibiting diverse clinical responses to specific therapeutic agents. Such heterogeneity reflects variable activation of signaling pathways. Consequently, RA physiopathology has been linked to many immune cells and factors, with controversial observations for interferons (IFNs). In this opinion article, we review the roles of these cytokines and the cells that produce them in light of recent data: clinical observations showing that expression of IFN-dependent genes does not reflect RA activity and RA mouse models in which the stimulation of IFN-dependent pathways provided disease protection. We suggest that epicutaneous stimulation of the IFN network is an attractive possibility to limit neutrophil infiltration or activation, thus providing therapeutic benefits to RA patients refractory to current therapies.