Hundred years ago, Leonhard Noon and John Freeman published their pioneering works on allergen-specific immunotherapy (ASIT) using grass pollen extracts. To honor their contribution to the development of ASIT as the only causal treatment of IgE-mediated allergies, we review the history of ASIT that started with the anecdotal descriptions of ASIT performed by the ancient king Mithridates (132-63 B.C.) and Jenner's development of a cowpox vaccine. Following Noon's and Freeman's first controlled human trials, ASIT was performed by a large number of modalities and with a myriad of pharmacologic preparations. These developments range from early aqueous pollen extracts and whole bee extracts to chemically modified allergens (allergoids) and various recombinant allergens. In addition to allergen-specific immunotherapy, non-specific immune response modifiers have been used in the past or are in the developmental stage. Also, currently many innovative experimental approaches of ASIT are studied in animal models and human in vitro systems and will hopefully further broaden the range of allergies that can be treated by ASIT, with enhanced efficacy and further reduced side-effects.