Burn injuries are the 4^th most common type of trauma experienced worldwide with severe burns accounting for more than 300,000 deaths every year. Debridement and wound coverage with an autologous graft is the gold standard of treatment but this is complicated in extensive surface area burns by a paucity of donor sites. Ready-made allogeneic skin substitutes are a promising treatment option in these instances although immune mediated rejection prevents them from acting as permanent wound coverage. Immune cell activation by antigens is crucial for immune-protection against pathological invasion however regulation of this interaction and induction of tolerance is essential in terms of autoimmunity, allergy, pregnancy and transplantation. Over the past decades we have seen advances in our knowledge of the molecular and cellular pathogenesis of tolerance. Indoleamine 2,3 dioxygenase (IDO) is one area where extensive success had been achieved in terms of understanding the mechanisms behind immune tolerance. IDO regulates the immune response through its negative effect on effector cell survival and upregulation of the regulatory T cell (Treg) population as a result of its catabolism of the essential amino acid tryptophan and accumulation of the tryptophan metabolites. It is expressed in a number of cell populations but facultative expression can be induced in skin cells, with the inflammatory mediator IFN-γ and other cytokines. Furthermore we have constructed skin substitutes populated with these IDO expressing fibroblasts. In this review we present a background on the mechanism of IDO governed immune tolerance, our methodology of IDO transduction and importantly our experience of tolerance with our IDO/ fibroblast skin substitute.