With the identification of regulatory T cells (Tr), the hunt for ways to specifically intervene in ongoing inflammatory responses has grown exponentially. Tr are attractive for therapy because they have the potential to control deleterious responses while preserving normal immune function. It has long been known that application of soluble antigen via the mucosa induces mucosal Tr that preserve systemic tolerance upon challenge with the same antigen. Mucosal Tr exhibit three major properties that allow selective control of immune responses. They are (1) adaptive—that is, they differentiate from naive T cells in the periphery;(2) antigen-specific—that is, specific for the (exogenous) antigen applied via the mucosa; and (3) versatile—that is, suppress, irrespective of ongoing Th1 or Th2 cytokine polarization. These powerful characteristics provide mucosal Tr with all requirements necessary to selectively interfere in an unbalanced immune system, as occurs in diseases ranging from autoimmunity to transplant rejection and allergy. Until now, however, translation into clinical applications has led to moderate success. This is primarily due to limited knowledge about the fundamental characteristics of these cells because of the lack of a differential marker. The initial stages of mucosal Tr induction, which may hold the key to discovering the identity of mucosal Tr and unraveling their function, are discussed in this review.