This chapter focuses on the CD4+ Th1/Th2/Th3 and Treg cells in mucosal immunoregulation. The development of mucosal immunity, inflammation, or tolerance to protein-based vaccines, viral and bacterial pathogens, allergens, and autoantigens requires T cells-including CD4-positive (CD4+) T helper (Th) cells, including Th1-/Th2-cell subsets, CD8+ cytotoxic T lymphocytes (CTLs), and other T-cell subpopulations. Regulatory T cells, which exhibit a CD4+ phenotype, can be classified as: naive, activated (effector), and memory. The Th1- and Th2-type cytokine-producing CD4+ T helper cells are involved in the induction of both cell-mediated immunity (CMI) and Ab immune responses. The IL-4, IL-5, IL-6, IL-10, and IL-13 play a central role in the induction of Ag-specific mucosal IgA Ab responses. Despite the induction of mucosal immunity, it is essential to have mechanisms that control and subsequently terminate these responses to avoid hyperimmune responses or inflammation. Mucosal tolerance is one of the major immune regulatory mechanisms for the maintenance host homeostasis. Thus, both the Th1- and Th2-type CD4+ T cells are involved in the induction and regulation of oral tolerance. © 2005 Elsevier Inc. All rights reserved.