Invariant natural killer T (iNKT) cells are innate cells that can bias an immune response toward inflammation or toward a negative regulatory response. iNKT cells can produce cytokines immediately on exposure to activating signals, but the role of iNKT cells in the differentiation of T regulatory (Treg) cells and peripheral tolerance was elucidated only within the past decade. The purpose of this review is to outline the current knowledge of how iNKT cells function in various tolerance paradigms. The roles of iNKT cell in anterior chamber-associated immune deviation (ACAID), oral tolerance, other tolerance systems, and autoimmune diseases is discussed.