Dysregulated Th1/Th17 responses, frequently paralleled by a reduction or absence of Treg cells, are key features of autoimmune disease. Conventional therapeutic approaches for autoimmune disease treatment are largely based on nonspecific immunosuppression leading to substantial side effects. Recent developments in the area of CD4(+) T-cell differentiation, together with experimental and preclinical findings with blockers of the IL-17 pathway and the use of Treg cell-based therapy, indicate that this CD4(+) effector subset could represent effective targets to restore immune tolerance. Here, the authors summarize the recent progress in our understanding of the pathways and cues that drive CD4(+) T-cell differentiation into specialized effectors, focusing on Th17 and Treg cells. The authors also discuss novel immunotherapeutic strategies based on targeting these T-cell subsets for autoimmune disease treatment.