The immune system and its increased response in atopic patients has resulted in significant morbidity for humans for centuries. Attempts to mitigate these affects by modifying the immune response has been ongoing for centuries as well. There are early suggestions of attempts to alter the immune system / response to toxins over the last 1000 years. Ehrlich in 1891 demonstrated the ability of mice to develop tolerance to ricin after escalating doses. In the early 1900s, several investigators demonstrated that progressive injections of larger doses of antigen led to protection from adverse outcomes. Initial methods for treatment of hay fever with immunotherapy were developed in 1911. These early studies paved the way for our current understanding of immunotherapy in which administration of increasing concentrations of antigen-specific extracts are used to modify the allergic response in atopic patients so as to diminish patient response to these antigens. This is indicated in the treatment of allergic rhinitis, allergic asthma, and stinging insect venom hypersensitivity. The method of delivery of the antigen also has varied throughout the years with the most common method being subcutaneous injection (SCIT). Other methods involved transconjunctival, intranasal, and bronchial immunotherapy. Oral allergen delivery was used initially in attempt to take advantage of the gut-associated lymphoid tissue (GALT), which would allow for exposure of antigen to the immune system. The concept though did not work well in evaluative studies for unclear reasons. Sublingual immunotherapy (SLIT) was introduced in the United States in the 1940s but did not gain widespread use until the last few decades. In the late 1980s, studies in Europe examined the use of sublingual immunotherapy with the World Health Organization, in 1998, concluding that sublingual immunotherapy (SLIT) was an effective means of immunotherapy administration. The exact method of SLIT effectiveness is not certain. Studies to date suggest the local immunological changes in the oral mucosa/sublingual space are a factor in the effect rather than systemic absorption, which is minimal. The immunologic changes of SLIT are similar to SCIT with decrease in antigen specific IgE, increase in IgG, increase in IL-10 as well as numerous other immune changes. One theory of action involves local dendritic cells capturing the allergen from oral mucosa and then migrating to proximal lymph nodes with IgG antibodies and T lymphocytes produced resulting in shift of immune response to TH-1 response (successful immunotherapy). The efficacy of SLIT has been well demonstrated with over 50 randomized double-blind placebo controlled trials. A MEDLINE review performed by Leatherman reported that 30 out of 36 trials involving children and adults demonstrated that SLIT was effective treatment for rhinitis, conjunctivitis, and/or asthma. Further, SLIT appears to be as effective as subcutaneous immunotherapy (SCIT) in these studies. In terms of the safety profile, SLIT safety studies suggest that SLIT has an improved safety profile over SCIT, which in it- self has an excellent safety record with a reported systemic reaction rate of 0.005% to 2.9%. With sublingual immunotherapy, there have been no deaths reported in the literature and only 14 severe general reactions. This includes studies in adults and children, including one by Di Rienzo involving 96,000 sublingual doses in pediatric patients with no significant side effects. The primary side effects that can occur involve local effects with oral irritation and pruritus. The techniques of administration of SLIT are similar to SCIT with escalation and maintenance phases although the escalation phase of SLIT much shorter other delivery methods lasting only 2-6 weeks. The antigen drops are used daily at home with the patient administering 3 drops under their tongue for 2 minutes and then swallowing or spitting the antigen. Therapy duration is similar to other modalities with the typical duration lasting 3 years. This is much more convenient than in office subcutaneous immunotherapy due to the ability for the patient to administer the medication at home without missing work or school. This also allows for immunotherapy to be given to patients who are needle phobic, including children. Overall, sublingual immunotherapy offers another treatment option for patients with atopic disease with an excellent safety profile in pediatric and adult populations, ease and convenience of drop administration at home, and extensive studies noting efficacy in pediatric and adult populations.