Allergic respiratory diseases affect approximately 15% of the US population. Allergen immunotherapy has been a treatment option for diseases such as allergic rhinitis, allergic asthma, and venom allergy for the last 100 years. During the first 75 years, conventional subcutaneous immunotherapy did not change much. However, the last 25 years has seen substantial growth in the development of alternatives to conventional subcutaneous immunotherapy. The addition of omalizumab, an anti-IgE mAb, to immunotherapy offers the potential for increased safety and efficacy. Activation of the innate immune system through Toll-like receptor agonists with and without specific allergens appears to improve the immunologic responses and clinical outcomes in patients with allergic diseases. The use of chemically altered allergens, allergoids, recombinant allergens, and relevant T-cell epitope peptides are all approaches that have yielded positive results. Finally, alternative modes of delivery hold promise, with sublingual immunotherapy rapidly approaching mainstream use in many countries. One thing is clear: the next century of immunotherapy will be vastly different from today’s current standard of care.