On encountering an antigen on the surface of antigen-presenting cells (and in the presence of IL-6 and TGF-β), naive T cells differentiate into TH17 cells. This event is associated with expression of the nuclear receptors RORγt and RORα. These receptors, particularly RORγt, are required for TH17-cell differentiation and for the expression of IL-23R and IL-17a, among other cytokines. Two studies1,2 show that digoxin and SR1001 bind RORγt, possibly by competing with the natural agonists of these receptors. By inhibiting the recruitment of co-activators and promoting the recruitment of co-repressors, these antagonists reduce RORγt transcriptional activity, TH17-cell differentiation and IL-17 production, and delay the onset and reduce the severity of autoimmune disease in mice.