Allergen specific immunotherapy (SIT) was first applied exactly a century ago by Noon and colleagues. Ever since, not much has changed in the original treatment protocol of subcutaneous injections with increasing doses of crude allergen extracts. This seems rather surprising since it is currently the only disease modifying treatment that offers long-term protection against allergic manifestations. Moreover, the efficacy of SIT is rather variable and appears to differ from patient to patient depending on the type of allergen, the type of allergic disease and on as yet unknown factors, including genetics. However, there is light at the end of the tunnel. Novel strategies are on their way to improve the burden of multiple subcutaneous injections by sublingual or intralymphatic administration, to improve its efficacy by using an adjuvant and to improve the standardization by using recombinant allergens. Despite its long history, the precise mechanism of action of SIT is still incompletely understood precluding rational improvement of SIT. To further dissect the mechanism(s) of action and to develop improved immunotherapeutic strategies, we have established a mouse model of SIT. Using this mouse model we have determined that the immunoregulatory cytokine interleukin-10 (IL-10) plays a critical role in the beneficial effects of SIT in this mouse model. IL-10 can be produced by regulatory T-cells (Treg), which have been shown to increase in allergic patients after SIT. Novel strategies to increase the efficacy of SIT using the mouse model will be presented and discussed.