The dynamic interplay between regulatory T cells (T regs) and effector T cells (T effs) governs the balance between tolerance and effector immune responses. Perturbations of T reg frequency and function or imbalances in T reg/T eff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. T regs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to T effs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient T reg control of T effs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7–driven increase in thymic T reg production and recruitment to inflamed tissues was too slow for disease prevention. Increased T eff over T reg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that T reg expansion mainly depended on this cytokine. IL-21R−/− cells were used to demonstrate that IL-21 promoted the maintenance of T effs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers T reg proliferation, whereas exaggerated IL-21 levels overwhelm T reg control by supporting T eff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.