The immune system has the daunting task of distinguishing between self and non-self. The mucosal immune system, present along the respiratory, gastrointestinal and genitourinary tracts, has the additional burden of coexisting with an abundance of dietary antigens and lumenal bacterial flora. A key feature of the mucosal immune system is its ability to remain tolerant to these antigens while retaining the capacity to repel pathogens effectively. Furthermore, tolerance generated at mucosal surfaces can translate to a more generalized systemic tolerance — a characteristic of great therapeutic potential, but with many unforeseen complexities that are explored in this review.