Post-transcriptional gene regulation by RNA-binding proteins is a fast and effective way to adapt gene expression and change cellular responses. These trans-acting factors have been involved in a number of cell fate decisions, and their mutation is often associated with the development of disease. The RNA-binding protein Roquin-1 has been found to be crucial in the maintenance of peripheral tolerance and the prevention of autoimmune disease. This review describes the molecular role of Roquin family proteins in the control of follicular T-helper cell differentiation. Here, we discuss the redundant regulation of Icos and Ox40 costimulatory receptor mRNAs by Roquin-1 and Roquin-2 proteins. A major focus is placed on the distinct activity of Roquin-1 or Roquin-2 proteins in the mouse models of conditional gene targeting. These recent data are then integrated into an interpretation of altered Roquin protein function in the sanroque mouse that expresses the Roquin-1 protein with just one amino acid substitution and, different from the Roquin-1-deficient mouse, develops lupus-like autoimmune disease.