Allergen immunotherapy (AIT) with whole allergens or allergen extracts has been in use for more than one hundred years. It is clinically efficacious and disease-modifying. However, AIT is also associated with a significant adverse events profile, including the potential to cause severe, systemic allergic reactions. One alternative to traditional whole-antigen AIT is peptide immunotherapy, which uses small synthetic peptide immunoregulatory epitopes (SPIRE) representing T cell epitopes from the allergen of interest. Peptide immunotherapy is being developed for the treatment of allergic and autoimmune diseases where pathogenesis is T cell-dependent. Short, soluble, monomeric peptide fragments avoid the problem of IgE-mediated adverse events (since the peptides will not cross-link allergen-specific IgE on the surface of effector cells such as mast cells and basophils). However, such peptides retain the capability to induce T cell tolerance and immunoregulation. In early clinical trials, efficacy has been demonstrated months to years after the cessation of a short course of treatment, supporting the conclusion that this approach is disease-modifying, changing the natural history of the disease. The improved safety profile of short peptides allows for larger molar-equivalent doses to be administered in shorter time frames than AIT; treatment can be completed in as few as four intradermal injections, while efficacy persists for two years or more.