Expression of forkhead transcription factor Foxp3 defines a distinct lineage of naturally arising regulatory T cells (nTregs) that is segregated from effector CD4+ T cells during early development in the thymus. It remains elusive whether nTregs can convert into effector cells by turning off their Foxp3 expression and, if so, whether Th17 is a default alternative fate choice. In this report we provide compelling evidence showing that effector T cell-polarizing cytokines IL-6 and IL-4 can act synergistically to induce marked downregulation and inactivation of Foxp3 gene expression in mouse nTregs, and consequently the loss of suppressor phenotype and functions. However, the resulting Foxp3− cells are not polarized and do not express IL-17 or other Th17-associated genes. Therefore, nTreg fate revision is not restricted to the Treg–Th17 axis and is likely to represent a rather broad phenomenon with divergent outcomes.