One hundred years have elapsed since specific allergen immunotherapy (SIT) was first employed and found to be effective in the treatment of allergic respiratory diseases. This cutting-edge issue of Immunology and Allergy Clinics offers a comprehensive review of this disease modifying treatment, exploring its history, status, and potential future. Topics covered include the mechanisms of subcutaneous allergen immunotherapy; the mechanisms of sublingual immunotherapy; optimizing efficacy of subcutaneous immunotherapy; preparation of allergen immunotherapy extraxcts; risk factors and subcutaneous immunotherapy safety; accelerated schedules and reducing risk with premedication (antihistamines, omalizumab, leucotriene antagonist); safety and efficacy of sublingual immunotherapy for allergic respiratory disease and other indications; monitoring clinical outcomes of specific immunotherapy; monitoring immunotherapy response with immunological parameters; socioeconomics and comparative effectiveness of immunotherapy; oral desensitization for food hypersensitivity; peptide and recombinant immunotherapy; intralymphatic and epicutaneous allergen-specific immunotherapy; peptide and recombinant immunotherapy; adjuvants and vector systems for allergy faccines; and future forms of immunotherapy.