Regulatory T (Treg) cells are essential for immunological tolerance and homeostasis. Although forkhead box (Fox)p3 is continually required to reinforce the Treg cell program, Treg cells can also undergo stimulus-specific differentiation that is regulated by transcription factors typically associated with the differentiation of conventional CD4⁺ T cells. This results in effector Treg (eTreg) cells with unique migratory and functional properties matched to the stimulus that elicited the initial response. Despite this functional and transcriptional heterogeneity, expression of the transcription factor B lymphocyte-induced maturation protein (Blimp)-1, a key player in late B cell and conventional T cell differentiation, is common to all eTreg cells. Here, we discuss the factors that control the differentiation of eTreg cells and their importance in disease settings.